MedWorm: Androgen Independent Prostate Cancer

Targeting monoamine oxidase A in advanced prostate cancer

Journal of Cancer Research and Clinical Oncology — Wed, 10 Mar 2010 16:10:15 +0100

Conclusion Our results support the possibility that anti-depressant drugs that target MAOA might find a new application in treating PCa. Content Type Journal ArticleCategory Original PaperDOI 10.1007/s00432-010-0835-6Authors Vincent Flamand, Stanford University School of Medicine Department of Urology, Stanford Medical Center Stanford CA 94305-5118 USAHongjuan Zhao, Stanford University School of Medicine Department of Urology, Stanford Medical Center Stanford CA 94305-5118 USADonna M. Peehl, Stanford University School of Medicine Department of Urology, Stanford Medical Center Stanford CA 94305-5118 USA Journal Journal of Cancer Research and Clinical OncologyOnline ISSN 1432-1335Print ISSN 0171-5216 (Source: Journal of Cancer Research and Clinical Oncology)

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Wnt-11 promotes neuroendocrine-like differentiation, survival and migration of prostate cancer cells

Molecular Cancer — Wed, 10 Mar 2010 00:00:00 +0100

Conclusions: These observations suggest that the increased level of Wnt-11 found in prostate cancer contributes to tumour recurrence by promoting NED, tumour cell survival and cell migration/invasion, and may provide an opportunity for novel therapy in prostate cancer. (Source: Molecular Cancer)

PSA Decrease with Fulvestrant Acetate in a Hormone-Resistant Metastatic Prostate Cancer Patient.

Onkologie — Fri, 19 Feb 2010 21:40:04 +0100

Conclusion: Fulvestrant was able to reduce the PSA level in this AIPC patient without any toxicity. PMID: 20164664 [PubMed - as supplied by publisher] (Source: Onkologie)

The transcriptional regulation of miR-21, its multiple transcripts, and their implication in prostate cancer.

Cell Cycle — Fri, 19 Feb 2010 15:30:30 +0100

Authors: Ribas J, Lupold SE MicroRNAs (miRNAs) are a natural part of the most recently discovered and global regulatory pathway known as RNA interference. Functional studies have shown how specific miRNAs can function as tumor suppressors or oncogenes and, correspondingly, deregulated miRNA profiles have been observed in prostate and other cancers. However, the upstream pathways which regulate miRNA expression are only currently being uncovered. The Androgen Receptor (AR) is a nuclear hormone receptor and transcription factor which plays a paramount role in prostate cancer (PCa) pathobiology. We performed high throughput miRNA microarray analysis on two AR-responsive cell lines to identified 16 candidate AR-regulated miRNAs.(1) One of the most androgen-induced candidates was a known on...

Tumor Suppressor Function of Androgen Receptor Coactivator ARA70{alpha} in Prostate Cancer.

The American Journal of Pathology — Thu, 18 Feb 2010 00:00:00 +0100

Authors: Ligr M, Li Y, Zou X, Daniels G, Melamed J, Peng Y, Wang W, Wang J, Ostrer H, Pagano M, Wang Z, Garabedian MJ, Lee P Androgen receptor (AR), a member of the steroid receptor family, is a transcription factor that has an important role in the regulation of both prostate cell proliferation and growth suppression. AR coactivators may influence the transition between cell growth and growth suppression. We have shown previously that the internally spliced ARA70 isoform, ARA70beta, promotes prostate cancer cell growth and invasion. Here we report that the full length ARA70alpha, in contrast, represses prostate cancer cell proliferation and anchorage-independent growth in vitro and inhibits tumor growth in nude mice xenograft experiments in vivo. Further, the growth inhibition by ARA7...

Inhibition of DHCR24/Seladin-1 impairs cellular homeostasis in prostate cancer

The Prostate — Wed, 17 Feb 2010 00:00:00 +0100

Seladin-1 belongs to a subgroup of androgen-dependent genes associated with anti-proliferative, pro-differentiation, and pro-apoptotic functions and plays a protective role against oncogenic stress. The present study aims to investigate the localization and expression of Seladin-1 protein in normal and tumoral human prostatic tissues as well as to explore its role in proliferation and steroid secretion in androgen-dependent (LnCaP) and androgen-independent (DU145) cell lines and in human prostate primary cell culture.Seladin-1 protein localization and expression were assessed on whole tissue sections by tissue array/immunohistochemistry and following immunofluorescence and Western blotting. Proliferation (Ki67 fluorescence labeling and cell counts) and steroid secretion (ELISA) were assess...

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Estrogen receptor-{beta} activated apoptosis in benign hyperplasia and cancer of the prostate is androgen independent and TNF{alpha} mediated [Medical_Sciences]

Proceedings of the National Academy of Sciences — Tue, 16 Feb 2010 18:56:48 +0100

Prostate cancer (PCa) and benign prostatic hyperplasia (BPH) are androgen-dependent diseases commonly treated by inhibiting androgen action. However, androgen ablation... (Source: Proceedings of the National Academy of Sciences)

The pure anti-androgen bicalutamide inhibits cyclin A expression both in androgen-dependent and -independent cell lines.

International Journal of Oncology — Thu, 04 Feb 2010 21:23:04 +0100

Authors: Katayama H, Murashima T, Saeki Y, Nishizawa Y We investigated the effects of testosterone and the pure anti-androgen, bicalutamide, on DNA synthesis and cell cycle in androgen-sensitive or -insensitive human and mouse cell lines by 3H-thymidine incorporation, flow cytometry, RT-PCR and Western blotting. In androgen-dependent mouse SC-3 cells, testosterone induced DNA synthesis, shift of cell cycle distribution from G0/G1 to S/G2/M and expression of cyclin A. The induction was preceded by that of fibroblast growth factor 8 (FGF-8), and completely blocked by monoclonal antibody to FGF-8. Dihydrotestosterone (DHT) induced cyclin A expression in androgen-sensitive human prostate cancer cells, but not in androgen-independent cell lines. Bicalutamide almost completely inhibited thes...

The molecular mechanism of Vav3 oncogene on upregulation of androgen receptor activity in prostate cancer cells.

International Journal of Oncology — Thu, 04 Feb 2010 21:22:39 +0100

Authors: Liu Y, Wu X, Dong Z, Lu S Our previous studies revealed that Vav3 oncogene is overexpressed in human prostate cancer, enhances androgen receptor (AR)-mediated signaling, and may play a role in prostate cancer development and progression. The purpose of this study was to determine the molecular mechanisms responsible for AR activation by Vav3. We found that interaction between N-terminus and C-terminus of AR is essential for its elevated activity stimulated by Vav3. The DH and PH domains of Vav3 are involved in direct interaction with AR. Both cytoplasmic and nuclear levels of AR and Vav3 are elevated and their nuclear localization is further stimulated by DHT in androgen-independent LNCaP-AI cells relative to their parental androgen-dependent LNCaP cells. Vav3 is colocalized w...

Prosaposin down-modulation decreases metastatic prostate cancer cell adhesion, migration, and invasion

Molecular Cancer — Thu, 04 Feb 2010 00:00:00 +0100

Conclusion: Our findings suggest that by a coordinated regulation of Cer levels, CathD and beta1A-integrin expression, and attenuation of "inside-out" integrin-signaling pathway, PSAP is involved in PCa invasion and therefore might be used as a molecular target for PCa therapy. (Source: Molecular Cancer)

Fibronectin confers survival against chemotherapeutic agents but not against radiotherapy in DU145 prostate cancer cells: Involvement of the insulin like growth factor-1 receptor

The Prostate — Mon, 01 Feb 2010 00:00:00 +0100

Tumor growth is influenced by an increase in cell proliferation and a reduction in apoptosis; both of which are affected by alterations in extracellular matrix (ECM). Our aim was to assess if the susceptibility of prostate cancer cells to apoptosis induced by either chemotherapeutics or radiotherapy was altered by changes in the ECM.Prostate cancer cell lines LNCaP and DU145 (androgen independent) cells were treated with chemotherapeutics (ceramide and docetaxel) or radiotherapy in the presence or absence of fibronectin, laminin, or vitronectin. Cell death was assessed using Trypan blue cell counting and apoptosis was confirmed by measuring PARP cleavage by Western immunoblotting (WIB). To identify a mechanism of action, changes in the abundance (WIB) or association (immunoprecipitation fo...

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Regulation of androgen receptor transactivity and mTOR-S6 kinase pathway by Rheb in prostate cancer cell proliferation

The Prostate — Mon, 01 Feb 2010 00:00:00 +0100

This study aimed to elucidate whether Rheb promotes proliferation of prostate cancer cells and can act as a potent therapeutic target in prostate cancer.Prostate cancer cell lines and human prostatic tissues were examined for the expression of Rheb. The effects of forced expression or knockdown of Rheb on cell proliferation were also examined. Semi-quantitative and quantitative RT-PCR were performed to evaluate mRNA expression. Western blotting was used to examine protein expression. Cell count and WST-1 assay were used to measure cell proliferation. Fluorescence-activated cell sorting was used to assess the cell cycle.Rheb mRNA and protein expression was higher in more aggressive, androgen-independent prostate cancer cell lines PC3, DU145, and C4-2, compared with the less aggressive LNCaP...

The radiation response of androgen-refractory prostate cancer cell line C4-2 derived from androgen-sensitive cell line LNCaP.

Asian Journal of Andrology — Mon, 01 Feb 2010 00:00:00 +0100

Authors: Xie BX, Zhang H, Yu L, Wang J, Pang B, Wu RQ, Qian XL, Li SH, Shi QG, Wang LL, Zhou JG Radiation therapy is a relatively effective therapeutic method for localized prostate cancer (PCa) patients. However, radioresistance occurs in nearly 30% of patients treated with potentially curative doses. Therapeutic synergy between radiotherapy and androgen ablation treatment provides a promising strategy for improving the clinical outcome. Accordingly, the androgen deprivation-induced signaling pathway may also mediate radiosensitivity in PCa cells. The C4-2 cell line was derived from the androgen-sensitive LNCaP parent line under androgen-depleted condition and had acquired androgen-refractory characteristics. In our study, the response to radiation was evaluated in both LNCaP and C4-2...

Regulation of HER expression and transactivation in human prostate cancer cells by a targeted cytotoxic bombesin analog (AN-215) and a bombesin antagonist (RC-3095)

International Journal of Cancer — Fri, 22 Jan 2010 00:00:00 +0100

Bombesin (BN) and gastrin-releasing peptide (GRP) have been shown to stimulate the growth of human prostate cancer in vivo and in vitro by mechanisms initiated by binding of the peptide to BN/GRP receptor (GRPR). GRPR is overexpressed in a variety of human cancers, including human prostatic carcinoma. This led us to evaluate the effectiveness of blocking GRPR and of chemotherapy targeted to GRPR in androgen-dependent (LNCaP) and androgen-independent (PC-3) prostate cancer cells, which exhibit different features of disease progression. Thus, we used a cytotoxic BN/GRP analog, AN-215, consisting of 2-pyrrolinodoxorubicin (AN-201) linked to BN-like carrier peptide, and a BN/GRP receptor antagonist, RC-3095. Semiquantitative RT-PCR and Western blotting revealed that mRNA and protein levels for...

Comprehensive evaluation of the role of EZH2 in the growth, invasion, and aggression of a panel of prostate cancer cell lines

The Prostate — Thu, 21 Jan 2010 00:00:00 +0100

In this study, a comprehensive evaluation of the phenotypic effects of EZH2 in a panel of five prostate cancer cell lines was performed. By using multiple cell lines, and examining overexpression and knockdown of EZH2 concurrently, a broad view of EZH2's role in prostate cancer was achieved.Overexpression of EZH2 led to more aggressive behaviors in all prostate cell lines tested. In contrast, downregulation of EZH2 reduced invasion and tumorigenicity of androgen-independent (AI) cell lines CWR22Rv1, PC3, and DU145, but not of androgen-dependent (AD) cell lines LAPC4 and LNCaP.Findings from this study suggest that AI prostate tumors are more dependent on EZH2 expression than AD tumors. Our observations provide an explanation for the strong correlation between EZH2 overexpression and advance...

E1A oncogene expression inhibits PTHrP P3 promoter activity and sensitizes human prostate cancer cells to TNF-induced apoptosis

International Urology and Nephrology — Fri, 15 Jan 2010 18:02:27 +0100

Abstract In the advanced stages of prostate cancer, tumor cells can evolve to become androgen-independent and resistant to injury-induced apoptosis. Tumor cell expression of parathyroid hormone-related protein (PTHrP) may contribute to the apoptosis phenotype. Expression of the adenovirus E1A oncogene repressed PTHrP promoter and mRNA expression in human PC-3 prostate cancer cells and increased the caspase 3 activation and sensitivity of these cells to apoptosis triggered by tumor necrosis factor alpha. These results suggest that strategies aimed at modulating PTHrP expression may increase the efficacy of innate immune effector mechanisms and proapoptotic, therapeutics in prostate cancer. Content Type Journal ArticleCategory Urology - Original PaperDOI 10.1007/s11255-009...

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Discovery and Mechanistic Characterization of a Novel Selective Nuclear Androgen Receptor Exporter for the Treatment of Prostate Cancer

Cancer Research — Thu, 14 Jan 2010 05:08:22 +0100

Advanced prostate cancers are invariably androgen independent, but they nonetheless retain reliance on the function of the androgen receptor, prompting efforts to find new ways to thwart the function of this factor. (Source: Cancer Research)

Ursolic acid overcomes Bcl-2-mediated resistance to apoptosis in prostate cancer cells involving activation of JNK-induced Bcl-2 phosphorylation and degradation

Journal of Cellular Biochemistry — Tue, 05 Jan 2010 00:00:00 +0100

Androgen-independent prostate cancers express high levels of Bcl-2, and this over-expression of Bcl-2 protects prostate cancer cells from undergoing apoptosis. Ursolic acid (UA) has demonstrated an anti-proliferative effect in various tumor types. The aim of this study is to evaluate the difference between UA-induced apoptosis in androgen-dependent prostate cancer cell line LNCaP cells and androgen-independent prostate cancer cell line LNCaP-AI cells and to reveal the molecular mechanisms underlying the apoptosis. We found that UA treatment in vitro can effectively induce apoptosis in LNCaP and LNCaP-AI cells. UA can overcome Bcl-2-mediated resistance to apoptosis in LNCaP-AI cells. Intrinsic apoptotic pathways can be triggered by UA treatment because c-Jun N-terminal kinase (JNK) is activ...

Telomerase enzyme inhibition (TEI) and cytolytic therapy in the management of androgen independent osseous metastatic prostate cancer

The Prostate — Thu, 31 Dec 2009 00:00:00 +0100

Recurrent prostate cancer can be osseous, androgen independent and lethal. The purpose is to discern the efficacy of synthetic small molecule telomerase enzyme inhibitors (TEI) alone or in combination with other cytotoxic therapies in controlling metastatic osseous prostate cancer.C4-2B was pre-treated with a match or mismatch TEI for 6 weeks and then inoculated into nude mice subcutaneously or intraosseously. In a separate experiment, untreated C4-2B was injected into femur of nude mice. The mice were divided into seven systemic "combination" treatment groups of control, Ad-BSP-E1a virus, docetaxel, mismatch and match TEI. Serum PSA was followed longitudinally. Histology analyses and histomorphometry were performed. Repeated measure analysis was applied for statistical analysis and Bonfer...

The developmental expression profile of PAX2 in the murine prostate

The Prostate — Wed, 16 Dec 2009 00:00:00 +0100

Nine transcription factors comprise the PAX gene family that regulate organogenesis. The urogenital system of PAX2 null male mice fails to develop properly. PAX2 is overexpressed in PC3 cells. Therefore, PAX2 is implicated in both prostate organogenesis and cancer. However, the expression pattern/profile of PAX2 in the prostate is unknown.PAX2/5/8 expression was surveyed in E16.5 male urogenital sinus (UGS) by RT-PCR. Prostate samples from 10 developmental stages in C3H male mice were used in quantitative reverse-transcript PCR (Q-PCR) and Western blotting (WB). RT-PCR and WB measured PAX2 expression in prostatic lobes or UGS layers, to identify local-regional expression patterns. Cytoplasmic versus nuclear expression was examined by WB. A castration series in adult C3H male mice and R1881...

(−)-Epigallocatechin-3-gallate induces Du145 prostate cancer cell death via downregulation of inhibitor of DNA binding 2, a dominant negative helix-loop-helix protein

Cancer Science — Mon, 14 Dec 2009 00:00:00 +0100

([minus])-Epigallocatechin-3-gallate (EGCG) is one of the major polyphenol components in green tea. It effectively induces apoptosis in prostate cancer cells. The anticancer effect of this reagent is appealing because it is a natural component of a popular daily beverage that has proven harmless for thousands of years, making it a good candidate chemopreventive agent. EGCG suppresses cell growth and causes cell death, but the mechanisms are not well characterized, especially in androgen-independent prostate cancer cells. In the present study, using Affymetrix genechip Hu133 2.0, we analyzed the gene expression patterns of the androgen-independent prostate cancer cell line Du145, treated with or without EGCG, and found 40 genes whose expression levels were altered (>twofold, either upregula...

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Conditionally replicating adenovirus therapy utilizing bone sialoprotein promoter (Ad-BSP-E1a) in an in vivo study of treating androgen-independent intraosseous prostate cancer.

Urologic Oncology — Sat, 05 Dec 2009 00:00:00 +0100

CONCLUSIONS: The CRAd Ad-BSP-E1a revealed potential in treating prostate cancer in this model system. Using viral or none-viral mediated gene therapy to treat prostate carcinoma continues to be a potential avenue to treat afflicted men with prostate cancer. PMID: 19963408 [PubMed - as supplied by publisher] (Source: Urologic Oncology)

Targeted Knockdown of EGR-1 Inhibits IL-8 Production and IL-8-mediated Invasion of Prostate Cancer Cells through Suppressing EGR-1/NF-{kappa}B Synergy [Mechanisms Of Signal Transduction]

Journal of Biological Chemistry — Fri, 04 Dec 2009 14:36:50 +0100

IL-8 produced by prostate cancer cells may be responsible for the androgen-independent growth of advanced prostate cancers. Accumulating evidence from microarray analyses and animal genetic models highlights the central involvement of the transcription factor early growth response-1 (EGR-1) in prostate carcinoma progression. It is unknown, however, whether knockdown of EGR-1 inhibits IL-8 production and IL-8-mediated tumor metastasis. Here we show that EGR-1 knockdown by a specific shRNA-Egr1 inhibited gene transcription and production of IL-8 by the human prostate cancer cell line DU145. Conversely, enforced expression of EGR-1 in EGR-1-lacking PC3 prostate cancer cells markedly enhanced IL-8 transcription and secretion. By using wild type and a series of mutant IL-8 promoter luciferase c...

Abstract C9: An in vitro model of osteoblastic bone metastasis in prostate cancer

Cancer Research — Wed, 02 Dec 2009 04:15:32 +0100

Prostate cancer progression is characterized by a striking affinity to spread to bone, where it forms metastases predominately of an osteoblastic phenotype, resulting in a significant source of morbidity. Currently, animal models for studying the development of these osteoblastic metastases are limited due to a lack of spontaneous osteoblastic metastasis development. In order to recapitulate osteoblastic metastasis development, an in vitro, three dimensional culture system was created utilizing silk fibroin scaffolds. LNCaP cells were seeded to silk scaffolds with human bone marrow derived mesenchymal stem cells (hMSCs) and cultured for 6 weeks. Examination after co-culture revealed through histological analysis that hMSCs underwent osteogenic differentiation in response to LNCaP paracrine...

A partner monoclonal antibody to Moab 730 kills 100% of DU145 and PC3 androgen-independent cancer cells.

Journal of Biosciences — Tue, 01 Dec 2009 00:00:00 +0100

Authors: Vyas HK, Pal R, Lohiya NK, Talwar GP A number of therapeutic options are available for patients with prostate carcinoma till the time that the tumour is hormone dependent. However, no fully effective therapy is available for the treatment of androgen-independent prostate carcinomas. Antibodies directed at epitopes unique to or overexpressed on the cancer cells could be of therapeutic utility. A monoclonal antibody (Moab) 2C4 has been generated, which binds with cells of two androgenindependent prostate cancers, DU145 and PC3, and does not bind to peripheral blood leukocytes (PBLs) of healthy donors. This antibody, along with the previously developed Moab 730, kills 100% of both DU145 and PC3 cells in the presence of complement and does not have a deleterious effect on PBLs of ...

Cytoprotective Mitochondrial Chaperone TRAP-1 As a Novel Molecular Target in Localized and Metastatic Prostate Cancer.

Am J Pathol — Mon, 30 Nov 2009 00:00:00 +0100

Authors: Leav I, Plescia J, Goel HL, Li J, Jiang Z, Cohen RJ, Languino LR, Altieri DC Molecular chaperones of the heat shock protein-90 (Hsp90) family promote cell survival, but the molecular requirements of this pathway in tumor progression are not understood. Here, we show that a mitochondria-localized Hsp90 chaperone, tumor necrosis factor receptor-associated protein-1 (TRAP-1), is abundantly and ubiquitously expressed in human high-grade prostatic intraepithelial neoplasia, Gleason grades 3 through 5 prostatic adenocarcinomas, and metastatic prostate cancer, but largely undetectable in normal prostate or benign prostatic hyperplasia in vivo. Prostate lesions formed in genetic models of the disease, including the transgenic adenocarcinoma of the mouse prostate and mice carrying pros...

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Differential phosphoprotein levels and pathway analysis identify the transition mechanism of LNCaP cells into androgen-independent cells

The Prostate — Fri, 20 Nov 2009 00:00:00 +0100

Androgen withdrawal can prolong life in men with advanced prostate cancer, but these remissions are temporary because the surviving cells progress as hormone-refractory cancer. The mechanisms that are involved in the transition of androgen-dependent prostate cancer into androgen-independent prostate cancer (AIPC) are not fully understood.To identify globally differentially expressed phosphoproteins in the androgen-independent prostate, to elucidate the molecular mechanisms that underlie the formation of AIPC and to identify new molecular targets that can be used to develop treatments for the disease.An androgen-independent LNCaP cell line, LNCaP-AI, was established using androgen ablation. Differentially expressed phosphoproteins in LNCaP cells and LNCaP-AI cells were enriched by immunopre...

Androgen receptor functioned as a suppressor in the prostate cancer cell line PC3 in vitro and in vivo.

Chinese Medical Journal — Fri, 20 Nov 2009 00:00:00 +0100

CONCLUSION: The AR might function as a tumor suppressor in PC3 cells both in vitro and in vivo. PMID: 19951614 [PubMed - in process] (Source: Chinese Medical Journal)

Suppressed tumour growth and enhanced chemosensitivity by RNA interference targeting Aurora-A in the PC3 human prostate cancer model

BJU International — Thu, 12 Nov 2009 00:00:00 +0100

To investigate the inhibitory effects of Aurora-A expression in prostate cancer cells on their growth and chemosensitivity. Aurora-A expression in radical prostatectomy specimens obtained from 193 patients were evaluated by immunohistochemical staining. We then established PC3 cells in which the expression vector containing short-hairpin RNA (shRNA) targeting Aurora-A was introduced (PC3/sh-A). The growth and the sensitivity to docetaxel in PC3/sh-A were compared with those in PC3 transfected with control vector alone (PC3/C). Immunohistochemistry showed that there were various levels of Aurora-A expression in most prostate cancer tissues, and the expression levels of Aurora-A in prostate cancer were significantly related to Gleason score. Expression levels of both Aurora-A mRNA and protei...

INTS6/DICE1 inhibits growth of human androgen-independent prostate cancer cells by altering the cell cycle profile and Wnt signaling

Cancer Cell International — Wed, 11 Nov 2009 00:00:00 +0100

Conclusions: These results show for the first time a link between INTS6/DICE1 function, cell cycle regulation and cell-cell communication involving members of the Wnt signaling pathway. (Source: Cancer Cell International)

Establishment and characterization of an androgen receptor-dependent, androgen-independent human prostate cancer cell line, LNCaP-CS10

The Prostate — Tue, 10 Nov 2009 00:00:00 +0100

Hormone refractoriness is a lethal event for advanced prostate cancer patients, but the mechanisms of the disease are not well elucidated, especially for the so-called "outlaw" pathways of androgen receptor (AR)-dependent, androgen-independent hormone-refractory prostate cancer.Androgen-dependent prostate cancer LNCaP cells were treated with bicalutamide under an androgen-depleted condition to obtain refractory cells. In the obtained cell line, LNCaP-CS10, we analyzed the effects of androgen and bicalutamide on cell growth and prostate-specific antigen (PSA) production. In addition, AR gene mutation, AR expression levels, and AR subcellular localizations were analyzed.In LNCaP-CS10, cell growth and PSA production were found under an androgen-depleted condition and were induced by both R188...

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Effect of zinc on regulation of insulin-like growth factor signaling in human androgen-independent prostate cancer cells.

International Journal of Clinical Chemistry — Tue, 10 Nov 2009 00:00:00 +0100

CONCLUSION: This study suggests that zinc decreases the survival of androgen-independent prostate cancer cells by modulating the expression of IGF system components and its signaling molecules. Thus, zinc may be qualified as a potential agent for the treatment of prostate cancer. PMID: 19913001 [PubMed - as supplied by publisher] (Source: International Journal of Clinical Chemistry)

CXC Receptor-1 Silencing Inhibits Androgen-Independent Prostate Cancer

Cancer Research — Thu, 29 Oct 2009 04:08:14 +0100

The CXC receptor-1 (CXCR1) is a coreceptor for interleukin-8 (IL-8) and is expressed on both normal and tumor cells. The function of CXCR1 in prostate cancer was investigated by silencing its expression, using RNA interference. We established stable cell colonies of PC-3 cells, depleted of CXCR1, using lentiviral plasmids (pLK0.1puro) generating small hairpin RNA (shRNA) against CXCR1 mRNA. Stable shRNA transfectants (PLK1–PLK5) that express significantly reduced CXCR1 mRNA (≥90% down) and protein (≥43% down) or vector-only transfectants (PC-3V) were characterized. PLK cells showed reduced cell proliferation (down, ≥66%), due to cell cycle arrest at G1-S phase, decreases in Cyclin D1, CDK4, phosphorylated Rb, and extracellular signal-regulated kinase 1/2 levels compared with...

Androgen-regulated gastrin-releasing peptide receptor expression in androgen-dependent human prostate tumor xenografts

International Journal of Cancer — Wed, 28 Oct 2009 00:00:00 +0100

In conclusion, expression of human GRPR in androgen-dependent PC xenografts is reduced by androgen ablation and is reversed by restoring the hormonal status of the animals. This knowledge suggests that hormonal therapy may affect GRPR expression in PC tissue making GRPR-based imaging and therapy especially suitable for non-hormonally treated PC patients. (Source: International Journal of Cancer)

Inhibiting TNF-mediated signaling: a novel therapeutic paradigm for androgen independent prostate cancer

Apoptosis — Fri, 23 Oct 2009 06:13:18 +0100

Abstract The tumor necrosis factor (TNF) receptor super family comprises of members that induce two distinct signaling cascades, leading to either cell survival or apoptosis. However, in prostate cancer (PCa), TNF-mediated prosurvival signaling is the predominant pathway that leads to cell survival and resistance to therapy. Although inhibition of TNF signaling by pharmacological agents or monoclonal antibodies has gained importance in the field of cancer therapy, toxicity to normal cells has impaired their extensive use for cancer treatment. We previously identified a natural, nontoxic compound psoralidin that inhibited viability and induced apoptosis in androgen independent prostate cancer (AIPC) cells. Thus, the goal of our study is to investigate whether psoralidin inh...

Weekly administration of docetaxel and epirubicin as first-line treatment for hormone-refractory prostate carcinoma.

Oncology Research — Fri, 09 Oct 2009 00:44:03 +0100

Authors: Neri B, Molinara E, Pantaleo P, Rangan S, Crisci A, Della Melina A, Raugei A, Villari D, Nicitat G Androgen-independent prostate carcinoma (AICP) is one of the tumors that continue to respond poorly to chemotherapy. Recently, protocols based on the use of docetaxel have significantly improved survival for patients in this disease. In other types of neoplastic disease, combined therapy with taxanes and anthracycline derivatives has been shown to produce additive effects in terms of growth inhibition, and superior tolerability when associated with weekly administration schedules. These findings prompted us to examine the tolerability and efficacy of weekly treatment of AICP with docetaxel (DOX) plus epirubicin (EPI). We enrolled 35 chemotherapy-naive men with AICP (mean age 72 y...

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STEAP4 regulates focal adhesion kinase activation and CpG motifs within STEAP4 promoter region are frequently methylated in DU145, human androgen-independent prostate cancer cells.

International Journal of Molecular Medicine — Thu, 01 Oct 2009 06:18:42 +0100

In this study, we report that STEAP4 expression is able to inhibit anchorage-independent cell growth. We also demonstrate that STEAP4 associates with focal adhesion kinase (FAK) and regulate the activity of FAK through Y397 phosphorylation. Furthermore, we show that CpG sequences in STEAP4 promoter region were frequently methylated in DU145, androgen-independent prostate cancer cells. Demethylation treatment induced STEAP4 expression in DU145, suggesting the possibility that STEAP4 expression in cancer cells is in part epigenetically regulated. Collectively, these data demonstrate a novel function of STEAP4 and that STEAP4 may play an important role in tumor malignancy. PMID: 19787193 [PubMed - in process] (Source: International Journal of Molecular Medicine)

Induction of bicalutamide sensitivity in prostate cancer cells by an epigenetic Pur[alpha]-mediated decrease in androgen receptor levels

The Prostate — Tue, 29 Sep 2009 23:00:00 +0100

Increased androgen receptor (AR) levels support resistance to apoptosis and hormone therapy in advanced prostate cancer (PC). We recently linked the overexpression of AR in androgen-independent LNCaP cells (AI-cells) and tissues from castration-resistant patients to decreased nuclear levels of Pur-alpha (Pur[alpha]) and loss from a protein complex bound to repressor sequences (ARS) in the 5[prime]-UTR of AR. Strategies to regain control of increased AR transcription may overcome resistance of AI-cells and improve treatment outcomes.MTT, real-time PCR, Western blot, ChIP, flow cytometry, and caspase 3/7 activation measured the effect on growth and targets of LBH589/bicalutamide treatment of AI-cells and androgen-dependent LNCaP cells (AD).Within 16 hr of treatment of AI-cells with low conce...

The Neuroendocrine-Derived Peptide Parathyroid Hormone-Related Protein Promotes Prostate Cancer Cell Growth by Stabilizing the Androgen Receptor

Cancer Research — Sun, 13 Sep 2009 23:00:00 +0100

In this study, we show that neuroendocrine-derived parathyroid hormone–related protein (PTHrP)–mediated signaling through the epidermal growth factor receptor (EGFR) and Src pathways contributes to the phenotype of advanced prostate cancer by reducing AR protein turnover. PTHrP-induced accumulation of AR depended on the activity of Src and EGFR and consequent phosphorylation of the AR on Tyr534. PTHrP-induced tyrosine phosphorylation of AR resulted in reduced AR ubiquitination and interaction with the ubiquitin ligase COOH terminus of Hsp70-interacting protein. These events result in increased accumulation of AR and thus enhanced growth of prostate cancer cells at low levels of androgen. [Cancer Res 2009;69(18):7402–11] (Source: Cancer Research)

Anticancer Agents from the Australian Tropical Rainforest: Spiroacetals EBC-23, 24, 25, 72, 73, 75 and 76.

Chemistry — Thu, 10 Sep 2009 23:00:00 +0100

Authors: Dong L, Schill H, Grange RL, Porzelle A, Johns JP, Parsons PG, Gordon VA, Reddell PW, Williams CM EBC-23, 24, 25, 72, 73, 75 and 76 were isolated from the fruit of Cinnamomum laubatii (family Lauraceae) in the Australian tropical rainforests. EBC-23 (1) was synthesized stereoselectively, in nine linear steps in 8 % overall yield, to confirm the reported relative stereochemistry and determine the absolute stereochemistry. Key to the total synthesis was a series of Tietze-Smith linchpin reactions. The novel spiroacetal structural motif, exemplified by EBC-23 (1), was found to inhibit the growth of the androgen-independent prostate tumor cell line DU145 in the mouse model, indicating potential for the treatment of refractory solid tumors in adults. PMID: 19750529 [PubMed - as...

Exogenous p27KIP1 expression induces anti-tumour effects and inhibits the EGFR/PI3K/Akt signalling pathway in PC3 cells.

Asian Journal of Andrology — Sun, 06 Sep 2009 23:00:00 +0100

In this study, we investigated whether exogenous p27 expression in the human androgen-independent prostate cancer PC3 cell line had any effect on cell growth, and we studied the molecular mechanisms involved. p27 expression was restored in PC3 cells by plasmid delivery. Cell proliferation and apoptosis were assessed in PC3 cells transfected with p27. We also investigated the effects of p27 on the epidermal growth factor receptor (EGFR)/phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathway in PC3 cells. By restoring p27 expression in PC3 cells, we observed that p27 reduced proliferation and induced arrest in G(0)/G(1) phase. Moreover, p27-transfected PC3 cells underwent apoptosis, as shown by flow cytometric analysis and western blotting analysis of Bcl-2, Bax, Bad, caspase-3 and poly...

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CTEN/tensin 4 expression induces sensitivity to paclitaxel in prostate cancer

The Prostate — Tue, 01 Sep 2009 23:00:00 +0100

Recently, we established paclitaxel-resistant prostate cancer cell lines (PC-3-TxR and DU145-TxR). To determine the mechanisms of paclitaxel resistance in PC-3-TxR cells, we compared the gene expression profiles between PC-3 and PC-3-TxR cells. Our results indicated that expression of the C-terminal tensin like protein (CTEN, tensin 4) gene was down-regulated by 10-fold in PC-3-TxR cells. We investigated the possibility that CTEN overexpression restores paclitaxel sensitivity.We investigated how knockdown and overexpression of CTEN in androgen-independent cell lines affect paclitaxel sensitivity by colony formation assay and growth inhibition assay. To determine the mechanisms by which CTEN affects paclitaxel sensitivity, we investigated the relationships between CTEN and F-actin or epider...

DNA methylation analysis of AR gene in androgen independent prostate cancer cell lines

Journal of Men's Health — Mon, 31 Aug 2009 23:00:00 +0100

Background: DNA methylation is one of the epigenetic mechanisms for controlling gene expression. The process of DNA methylation involves the covalent addition of a methyl group in position 5 to cytosine giving rise to 5-methylcytosine (5mC). 5mC often occurs especially in CpG dinucleotides of the promoter regulation region in many genes and gene inactivation may follow from such CpG methylation. (Source: Journal of Men's Health)

Prolonging androgen sensitivity in prostate cancer – a role for COX inhibitors?

ANZ Journal of Surgery — Sun, 30 Aug 2009 23:00:00 +0100

Conclusion: This study does not support a role for COX-2 inhibitors in prolonging androgen responsiveness in prostate cancer. (Source: ANZ Journal of Surgery)

Intermittent hormone therapy and its place in the contemporary endocrine treatment of prostate cancer

Surgical Oncology — Thu, 27 Aug 2009 12:54:41 +0100

Abstract: Castration results in dangerous and disabling side effects. Deferred hormone therapy has been shown to be associated with decreased survival. Intermittent hormone therapy (IHT) was attempted initially to reduce morbidity of treating metastatic prostate cancer with stilboestrol. Preclinical work using castrate mice with hormone sensitive prostate tumours demonstrated that pulses of testosterone delayed the onset of androgen independent growth and PSA production in these mice. This led to development of clinical treatment protocols for use in phase II trials by a number of centres in a variety of clinical scenarios. These phase II trials demonstrated apparent safety of this approach, prompting several large scale RCTs. Thus far no difference in survival has been demonstrated betwee...

The Neuroendocrine-Derived Peptide Parathyroid Hormone-Related Protein Promotes Prostate Cancer Cell Growth by Stabilizing the Androgen Receptor.

Cell Research — Mon, 24 Aug 2009 23:00:00 +0100

In this study, we show that neuroendocrine-derived parathyroid hormone-related protein (PTHrP)-mediated signaling through the epidermal growth factor receptor (EGFR) and Src pathways contributes to the phenotype of advanced prostate cancer by reducing AR protein turnover. PTHrP-induced accumulation of AR depended on the activity of Src and EGFR and consequent phosphorylation of the AR on Tyr(534). PTHrP-induced tyrosine phosphorylation of AR resulted in reduced AR ubiquitination and interaction with the ubiquitin ligase COOH terminus of Hsp70-interacting protein. These events result in increased accumulation of AR and thus enhanced growth of prostate cancer cells at low levels of androgen. [Cancer Res 2009;69(18):OF1-10]. PMID: 19706771 [PubMed - as supplied by publisher] (Source: Cell...

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Expression of TRPC6 in benign and malignant human prostate tissues.

Asian Journal of Andrology — Sun, 23 Aug 2009 23:00:00 +0100

Authors: Yue D, Wang Y, Xiao JY, Wang P, Ren CS We investigated the expression of transient receptor potential canonical 6 (TRPC6) protein in benign and malignant human prostate tissues and in prostate cancer cell lines and the association with the stage, grade and androgen responsiveness of the tumors. Immunohistochemical techniques, Western blot and reverse transcription polymerase chain reaction (RT-PCR) were used to investigate TRPC6 expression. TRPC6 protein was detected in 9 of 20 (45.0%) of benign prostatic hyperplasia (BPH) cases, and there was a significant difference compared with prostate cancer (129 of 149 [86.6%])(P < 0.01). TRPC6 expression was associated with the histological grade and extraprostatic extension (P < 0.01). Tumors of higher stage tended to have a hig...

Intrinsic expression of host genes and intronic miRNAs in prostate carcinoma cells

Cancer Cell International — Tue, 11 Aug 2009 23:00:00 +0100

Conclusion: Our results suggest that miRNA expression profiles may not predict intrinsic hormone-sensitive environment of PCa cells. More importantly, our data indicate the possibility of additional novel mechanisms for intronic miRNA processing in PCa cells. (Source: Cancer Cell International)

Depletion of intrinsic expression of interleukin-8 in prostate cancer cells causes cell cycle arrest, spontaneous apoptosis and increases the efficacy of chemotherapeutic drugs

Molecular Cancer — Thu, 30 Jul 2009 23:00:00 +0100

Conclusion: These results show the pervasive role of IL-8 in promoting tumor cell survival, and resistance to cytotoxic drugs, regardless of the cytotoxic mechanism of antiproliferative drugs, and point to potential therapeutic significance of IL-8 depletion in men with AIPC. (Source: Molecular Cancer)

Key Event In Prostate Cancer Progression Discovered

ScienceDaily Headlines — Tue, 28 Jul 2009 12:00:00 +0100

Researchers have discovered how hormone-dependent prostate cancer advances to the incurable hormone-independent disease state. The study shows that in androgen-independent prostate cancer, androgen receptors are reprogrammed to regulate genes involved in a later phase of cell division. A small epigenetic change in a gene called UBE2C is responsible for this reprogramming. Increased expression of that gene correlated with progression to the hormone-independent phase. (Source: ScienceDaily Headlines)

Androgen Receptor Regulates a Distinct Transcription Program in Androgen-Independent Prostate Cancer

Cell — Fri, 24 Jul 2009 03:00:07 +0100

Qianben Wang, Wei Li, Yong Zhang, Xin Yuan, Kexin Xu, Jindan Yu, Zhong Chen, Rameen Beroukhim, Hongyun Wang, Mathieu Lupien, Tao Wu, Meredith M. Regan, Clifford A. Meyer, Jason S. Carroll, Arjun Kumar Manrai, Olli A. Jänne, Steven P. Balk, Rohit Mehra, Bo Han, Arul M. Chinnaiyan, Mark A. Rubin, Lawrence True, Michelangelo Fiorentino, Christopher Fiore, Massimo Loda, Philip W. Kantoff, X. Shirley Liu, Myles Brown. The evolution of prostate cancer from an androgen-dependent state to one that is androgen-independent marks its lethal progression. The androgen receptor (AR) is essential in both, though its func.... (Source: Cell)

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Scientists discover key event in prostate cancer progression

EurekAlert! - Medicine and Health — Thu, 23 Jul 2009 04:00:00 +0100

(Ohio State University Medical Center) Researchers at the Ohio State University Comprehensive Cancer Center and Dana-Farber Cancer Institute have discovered how hormone-dependent prostate cancer advances to the incurable hormone-independent disease state. The study shows that in androgen-independent prostate cancer, androgen receptors are reprogrammed to regulate genes involved in a later phase of cell division. A small epigenetic change in a gene called UBE2C is responsible for this reprogramming. Increased expression of that gene correlated with progression to the hormone-independent phase. (Source: EurekAlert! - Medicine and Health)

Cyr61 downmodulation potentiates the anticancer effects of zoledronic acid in androgen-independent prostate cancer cells

International Journal of Cancer — Sat, 18 Jul 2009 23:00:00 +0100

We have analyzed the gene modulation induced by zoledronic acid (ZOL) in androgen-resistant prostate cancer PC3 cells with cDNA microarray platform to identify new molecular targets of ZOL in prostate cancer. The gene coding for cysteine-rich, angiogenic inducer, 61 (CYR61) resulted highly downregulated with a fold change of 5.58. Therefore, we have studied the effects of ZOL on CYR61 protein product, and we have found that CYR61 protein expression was decreased significantly after exposure to ZOL. The effect of ZOL on CYR61 expression was dose and time dependent was due to a reduced transcriptional activity of CYR61 promoter. Moreover, the effects induced by ZOL were paralleled by decreased activation of Ras-Raf-1- and Akt-dependent pathways that was dependent from isoprenylation inhibiti...

Detection of Intracellular Granularity Induction in Prostate Cancer Cell Lines by Small Molecules Using the HyperCyt(R) High-Throughput Flow Cytometry System

Journal of Biomolecular Screening — Thu, 16 Jul 2009 23:00:00 +0100

Prostate cancer is a leading cause of death among men due to the limited number of treatment strategies available for advanced disease. Discovery of effective chemotherapeutics involves the identification of agents that inhibit cancer cell growth. Increases in intracellular granularity have been observed during physiological processes that include senescence, apoptosis, and autophagy, making this phenotypic change a useful marker for identifying small molecules that induce cellular growth arrest or death. In this regard, epithelial-derived cancer cell lines appear uniquely susceptible to increased intracellular granularity following exposure to chemotherapeutics. We have established a novel flow cytometry approach that detects increases in side light scatter in response to morphological ch...

Matrix Protein CCN1 Is Critical for Prostate Carcinoma Cell Proliferation and TRAIL-Induced Apoptosis.

Cell Research — Mon, 06 Jul 2009 23:00:00 +0100

Authors: Franzen CA, Chen CC, Todorovic V, Juric V, Monzon RI, Lau LF Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) plays an important role in immune surveillance and preferentially induces apoptosis in cancer cells over normal cells, suggesting its potential in cancer therapy. However, the molecular basis for its selective killing of cancer cells is not well understood. Recent studies have identified the CCN family of integrin-binding matricellular proteins as important regulators of cell behavior, including cell adhesion, proliferation, migration, differentiation, and survival. We show here that CCN1 (CYR61) supports the adhesion of prostatic carcinoma cells as an adhesion substrate through integrins and heparan sulfate proteoglycans. Knockdown of CCN1 expression in...

Primary research on chinese medicine treatment of androgen-independent prostate cancer

Chinese Journal of Integrative Medicine — Wed, 01 Jul 2009 05:49:32 +0100

Content Type Journal ArticleCategory Feature ArticleDOI 10.1007/s11655-009-0168-yAuthors Shu-wu Zhang, Chengdu University of Traditional Chinese Medicine Chengdu 610075 ChinaShi-yi Zhou, Chengdu University of Traditional Chinese Medicine Chengdu 610075 ChinaJi-chun Shao, Chengdu University of Traditional Chinese Medicine Chengdu 610075 ChinaXiao-wei Qu, Chengdu University of Traditional Chinese Medicine Chengdu 610075 China Journal Chinese Journal of Integrative MedicineOnline ISSN 1993-0402Print ISSN 1672-0415 Journal Volume Volume 15 Journal Issue Volume 15, Number 3 / June, 2009 (Source: Chinese Journal of Integrative Medicine)

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Molecular biology underlying the clinical heterogeneity of prostate cancer: an update.

Archives of Pathology and Laboratory Medicine — Tue, 30 Jun 2009 23:00:00 +0100

CONCLUSIONS: Prostatic adenocarcinoma is a heterogeneous group of neoplasms with a broad spectrum of pathologic and molecular characteristics and clinical behaviors. Numerous mechanisms contribute to the development of resistance to androgen ablation therapy, resulting in ligand-independent reactivation of the androgen receptor, including amplification, mutation, phosphorylation, and activation of coreceptors. Multiple translocations of members of the ETS oncogene family are present in approximately half of clinically localized prostate cancers. TMPRSS2:ERG gene rearrangement appears to be an early event in prostate cancer and is not observed in benign or hyperplastic prostatic epithelium. Duplication of TMPRSS2:ERG appears to predict a worse prognosis. The relationship between TMPRSS2:ERG...

Key targets of hormonal treatment of prostate cancer. Part 1: the androgen receptor and steroidogenic pathways

BJU International — Wed, 24 Jun 2009 23:00:00 +0100

The objective of this review is to provide an understanding of the mechanisms that prostate cancer cells use to bypass androgen-deprived conditions. We searched PubMed for experimental and clinical studies that describe the molecular changes that lead to CRPC. CRPC remains dependent on a functional androgen receptor (AR), AR-mediated processes, and on the availability of intraprostatic intracellular androgens. CRPCs might acquire different (molecular) mechanisms that enable them to use intracellular androgens more efficiently (AR amplification, AR protein overexpression, AR hypersensitivity), use alternative splice variants of the AR protein to mediate androgen-independent AR functioning, and have altered co-activator and co-repressor gene and protein expression. Furthermore, CRPCs might h...

Effects of cIAP-1, cIAP-2 and XIAP triple knockdown on prostate cancer cell susceptibility to apoptosis, cell survival and proliferation

Molecular Cancer — Mon, 22 Jun 2009 23:00:00 +0100

Conclusion: Simultaneous knock down of the IAPs not only sensitised the PC-3 to TRAIL but also inhibited their proliferation rates and clonogenic survival. The inability to alter sensitivity to other triggers of apoptosis suggests that this effect is specific for death receptor pathways and knock down might facilitate immune-surveillance mechanisms to counter cancer progression and, in combination with therapeutic approaches using TRAIL, could represent an important treatment strategy. (Source: Molecular Cancer)

Hesperidin suppressed proliferations of both Human breast cancer and androgen-dependent prostate cancer cells

Phytotherapy Research — Sun, 21 Jun 2009 23:00:00 +0100

This study investigated whether hesperidin affected the proliferation of MCF-7 human breast cancer cells transfected with green fluorescent protein (GFP)/[agr]-tubulin (MCF-7-GFP-Tubulin cells), androgen-independent PC-3 and DU-145 prostate cancer cells, and androgen-dependent LNCaP prostate cancer cells. The results were as follows. (1) Hesperidin inhibited the proliferation of MCF-7-GFP-Tubulin cells, probably not through an antimitotic mechanism. (2) Hesperidin also inhibited both basal and testosterone-induced proliferation of LNCaP cells. (3) However, hesperidin did not significantly affect the cell proliferation of two hormone-independent prostate cancer cells, PC-3 and DU-145. It is concluded that hesperidin can inhibit the proliferation of breast cancer cells through mechanisms oth...

Phosphorylation of Bcl-2 and activation of caspase-3 via the c-Jun N-terminal kinase pathway in ursolic acid-induced DU145 cells apoptosis.

Biochimie — Thu, 18 Jun 2009 23:00:00 +0100

Authors: Zhang YX, Kong CZ, Wang HQ, Wang LH, Xu CL, Sun YH There is currently no successful therapy for androgen-independent prostate cancer. Ursolic acid (UA), a pentacyclic triterpenoid compound, has been shown to have an anti-proliferative effect on various tumors. We investigated the effect of UA on cell viability in the human hormone-refractory prostate cancer cell line DU-145, as well as the molecular mechanisms underlying its growth inhibiting effect. We demonstrated that UA induces apoptosis and the activation of caspase-3 in DU145 cells. UA also causes the activation of c-Jun N-terminal kinase (JNK), but has no effect on extracellular signal-regulated protein kinases (ERK1/2) and p38 MAP kinases (p38). UA-induced JNK activation could result in Bcl-2 phosphorylation (Ser70) an...

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Inositol hexaphosphate downregulates both constitutive and ligand-induced mitogenic and cell survival signaling, and causes caspase-mediated apoptotic death of human prostate carcinoma PC-3 cells

Molecular Carcinogenesis — Wed, 17 Jun 2009 23:00:00 +0100

Constitutively active mitogenic and prosurvival signaling cascades due to aberrant expression and interaction of growth factors and their receptors are well documented in human prostate cancer (PCa). Epidermal growth factor (EGF) and insulin-like growth factor-1 (IGF-1) are potent mitogens that regulate proliferation and survival of PCa cells via autocrine and paracrine loops involving both mitogen-activated protein kinase (MAPK)- and Akt-mediated signaling. Accordingly, here we assessed the effect of inositol hexaphosphate (IP6) on constitutive and ligand (EGF and IGF-1)-induced biological responses and associated signaling cascades in advanced and androgen-independent human PCa PC-3 cells. Treatment of PC-3 cells with 2 mM IP6 strongly inhibited both growth and proliferation and decrease...

Mammalian target of rapamycin: A new target in prostate cancer

Urologic Oncology: Seminars and Original Investigations — Mon, 15 Jun 2009 00:00:00 +0100

Abstract: Molecular targets in prostate cancer are continually being explored, especially in the poor-prognosis androgen-independent phase of the disease, for which there are currently few therapeutic options. One such target is the mammalian target of rapamycin (mTOR) protein. Activation of mTOR results in sequential activation of downstream molecules, which ultimately results in cell division. In this review, we consider the rationale for pursuing mTOR as a therapeutic target in prostate cancer and summarize preclinical and clinical studies of mTOR inhibition in prostate cancer. (Source: Urologic Oncology: Seminars and Original Investigations)

Treatment of prostate cancer cells with adenoviral vector-mediated antisense RNA using androgen-dependent and androgen-independent promoters

Medical Oncology — Thu, 11 Jun 2009 16:14:37 +0100

Abstract The present study was designed to develop a novel antisense approach to prostate cancer therapy. We constructed ODC/AdoMetDC double antisense RNA recombinant adenovirus mediated by a prostate-specific androgen-dependent promoter (pADxsi-P2-AdoMetDC-ODC-PolyA) or a prostate-specific androgen-independent promoter (pADxsi-P1-AdoMetDC-ODC-PolyA). Western blot analysis was performed to detect the ODC and AdoMetDC protein levels. The growth curves for each group of cells were determined by MTT assay. Flow cytometry was conducted to detect cell apoptosis, proliferation, and cell cycle distribution in order to demonstrate the effects of the recombinant adenoviruses on the prostate cancer cells. RT-PCR, Western blotting, MTT, and tumor growth inhibition assay in nude mice ...

Mammalian target of rapamycin: A new target in prostate cancer.

Urologic Oncology — Wed, 10 Jun 2009 23:00:00 +0100

Authors: Rai JS, Henley MJ, Ratan HL Molecular targets in prostate cancer are continually being explored, especially in the poor-prognosis androgen-independent phase of the disease, for which there are currently few therapeutic options. One such target is the mammalian target of rapamycin (mTOR) protein. Activation of mTOR results in sequential activation of downstream molecules, which ultimately results in cell division. In this review, we consider the rationale for pursuing mTOR as a therapeutic target in prostate cancer and summarize preclinical and clinical studies of mTOR inhibition in prostate cancer. PMID: 19523861 [PubMed - as supplied by publisher] (Source: Urologic Oncology)

Inhibin-alpha subunit expression linked to advanced prostate cancer

MedWire News - Prostate Cancer — Wed, 03 Jun 2009 00:00:00 +0100

Inhibin-alpha subunit has pro-tumorigenic and pro-metastatic effects in prostate cancer and is associated with androgen-independent metastatic disease, Australian study findings indicate. (Source: MedWire News - Prostate Cancer)

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Inhibin-alpha subunit expression linked to advanced prostate cancer

MedWire News - Oncology — Wed, 03 Jun 2009 00:00:00 +0100

Immunotherapy data may signal new era in advanced prostate cancer care

UrologyTimes - Prostate Cancer — Mon, 01 Jun 2009 04:00:00 +0100

Results of a milestone study on the use of an experimental form of immunotherapy may usher in a new era in the management of androgen-independent prostate cancer. (Source: UrologyTimes - Prostate Cancer)

Suppression of ErbB-2 in androgen-independent human prostate cancer cells enhances cytotoxic effect by gemcitabine in an androgen-reduced environment

Cancer Letters — Sun, 24 May 2009 23:00:00 +0100

We examined the efficacy of combination treatments utilizing cytotoxic drugs plus inhibitors to members of the ErbB–ERK signal pathway in human prostate cancer (PCa) LNCaP C-81 cells. Under an androgen-reduced condition, 50nM gemcitabine caused about 40% growth suppression on C-81 cells. Simultaneous treatment of gemcitabine plus 10μM AG825 produced 60% suppression (p (Source: Cancer Letters)

Prostate cancer: Resistance is (hopefully) futile

Nature Reviews Cancer — Sat, 23 May 2009 02:11:32 +0100

Nature Reviews Cancer 9, 386 (2009). doi:10.1038/nrc2668 Author: Sarah Seton-Rogers Anti-androgens, such as bicalutamide, are used to treat advanced prostate cancer, but eventually the tumours become androgen independent (known as castration-resistant prostate cancer, CRPC). Three recent papers have identified promising new ways in which the androgen receptor (AR) might be targeted to overcome resistance. (Source: Nature Reviews Cancer)

Clinical research on treatment of advanced androgen independent prostate cancer with Docetaxel and Thalidomide

The Chinese-German Journal of Clinical Oncology — Fri, 15 May 2009 05:57:40 +0100

Conclusion The regimen of Docetaxel combined with Thalidomide was effective and tolerable in the treatment of advanced AIPC. Content Type Journal ArticleDOI 10.1007/s10330-009-0028-4Authors Jing Tian, The People’s Hospital of Leshan Department of Oncology Leshan 614000 ChinaDonghai Teng, The People’s Hospital of Leshan Department of Urology Leshan 614000 ChinaXiangdong Shu, The People’s Hospital of Leshan Department of Oncology Leshan 614000 ChinaHong Lu, The People’s Hospital of Leshan Department of Oncology Leshan 614000 ChinaHui Chen, The People’s Hospital of Leshan Department of Oncology Leshan 614000 ChinaPeng Guo, Chengdu Friendship Hospital Chengdu 610041 China Journal The Chinese-German Journal of Clinical OncologyOnline ISSN 1613-9089Print ISSN...

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Provenge Shows Survival Benefit in Prostate Cancer

Internal Medicine News — Fri, 15 May 2009 04:00:00 +0100

CHICAGO — Autologous active cellular immunotherapy with sipuleucel-T, the controversial investigative agent with the brand name Provenge, extended survival by a median of 4.1 months in men with metastatic androgen-independent prostate cancer, according to the most recent data from the IMPACT study. (Source: Internal Medicine News)

Osteosclerotic prostate cancer metastasis to murine bone are enhanced with increased bone formation

Clinical and Experimental Metastasis — Thu, 07 May 2009 06:05:52 +0100

Abstract Spontaneous development of osteoblastic lesions of prostate cancer (PCa) in mice is modeled by orthotopic (intraprostatic) deposition of neoplastic cells followed by an extremely long latency associated with low incidence of spontaneous bone metastasis. Intracardial injection results in overt bone metastases only with osteoclastic PCa cells (i.e., PC-3). Herein, we report that androgen independent osteoblastic PCa cells readily colonize bone when in a high remodeling state. SCID/Beige mice were subjected to periods of intermittent human parathyroid hormone 1–34 (hPTH) exposure, followed by an intracardiac infusion of osteoblastic C4-2 PCa cells. At the time of PCa infusion, analysis of bone turnover markers from mice treated with hPTH revealed significant increa...

Ubiquitous mitochondrial creatine kinase is overexpressed in the conditioned medium and the extract of LNCaP lineaged androgen independent cell lines and facilitates prostate cancer progression

The Prostate — Mon, 04 May 2009 04:00:00 +0100

Androgen independent prostate cancer (AIPC) is not responsive to androgen ablation therapy. The biomarkers of AIPC are lack. Numerous proteomics studies have focused on finding new markers of AIPC and exploring their possible functions, but little is known about the difference between conditioned medium (CM) from AIPC and androgen dependent prostate cancer (ADPC) cells.We performed a proteome analysis of CM from LNCaP, C4-2, and C4-2B cells by a two dimensional electrophoresis based technology. Western blots and immunohistochemical studies were employed to explore the expression pattern of the identified protein in prostate cancer cell lines and clinical specimens, respectively. Then we examined the possible roles and mechanisms of the ubiquitous mitochondrial creatine kinase (uMtCK) in vi...

Penta-O-galloyl-beta-D-glucose induces S- and G1-cell cycle arrests in prostate cancer cells targeting DNA replication and cyclin D1

Carcinogenesis — Thu, 30 Apr 2009 04:00:00 +0100

We have recently shown that penta-1,2,3,4,6-O-galloyl-beta-D-glucose (PGG), a naturally occurring hydrolyzable gallotannin, inhibited the in vivo growth of human androgen-independent p53-mutant DU145 prostate cancer (PCa) xenograft in athymic nude mice without adverse effect on their body weight. We have also shown that PGG induced caspase-mediated apoptosis in the DU145 cells and the androgen-dependent human p53-wild-type LNCaP cells. Here, we investigated the cell cycle effects of PGG in these and other PCa cells. Our data show that treatment with subapoptotic doses of PGG induced S-arrest, whereas higher doses of PGG induced not only S-arrest but also G1 arrest. We show, for the first time, that irrespective of the p53 functional status of the PCa cell lines, PGG exerted a rapid (within...

The prostatic environment suppresses growth of androgen-independent prostate cancer xenografts: An effect influenced by testosterone

The Prostate — Wed, 29 Apr 2009 04:00:00 +0100

Interactions between prostate cancer cells and their surrounding stroma play an important role in the growth and maintenance of prostate tumors. To elucidate this further, we investigated how growth of androgen-dependent (AD) LNCaP and androgen-independent (AI) LNCaP-19 prostate tumors was affected by different microenvironments and androgen levels.Tumor cells were implanted subcutaneously and orthotopically in intact and castrated immunodeficient mice. Orthotopic tumor growth was followed by magnetic resonance imaging (MRI). Gene expression in the tumors was evaluated by means of microarray analysis and microvessel density (MVD) was analyzed using immunohistochemistry.The results showed that LNCaP-19 tumors grew more rapidly at the subcutaneous site than in the prostate, where tumors were...

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Id-1 expression in androgen-dependent prostate cancer is negatively regulated by androgen through androgen receptor

Cancer Letters — Wed, 22 Apr 2009 09:10:25 +0100

This study discovered that Id-1 expression in androgen-dependent prostate cancer decreased immediately after androgen deprivation but increased after longer androgen deprivation both in vivo and in vitro. Id-1 expression in androgen-independent LNCaP cells was about 6 fold as that in their parental cells. As was the case with LNCaP cells, when androgen receptor (AR) was introduced into AR-negative PC-3 cells, dihydrotestosterone inhibited while flutamide increased Id-1 expression. Thus, Id-1 expression in androgen-dependent prostate cancer was negatively regulated by androgen in a receptor-dependent way. The re-increased Id-1 might partially contribute to the emergence of androgen-independent prostate cancer after longer androgen deprivation therapy. (Source: Cancer Letters)

A Potential New Target For Treatment Of Hormone Refractory Prostate Cancer

Cancercompass News: Prostate Cancer — Sat, 18 Apr 2009 05:00:00 +0100

A new study identifies a protein that modifies the androgen receptor (AR) and influences its ability to regulate target genes linked with the progression of prostate cancer. The research, published by Cell Press in the April 7th issue of the journal Cancer Cell, may also drive creation of new strategies for the treatment of advanced prostate cancer that no longer responds to traditional anti-hormone therapies. The AR is an important mediator for the development and progression of prostate cancer, including the progression to the aggressive and often lethal androgen-independent form of the disease. "Androgen ablation therapy is the most common treatment for advanced prostate cancer," offers senior study author, Dr. Yun Qiu from the Univer... (Source: Cancercompass News: Prostate Cancer)

RelB Enhances Prostate Cancer Growth: Implications for the Role of the Nuclear Factor-{kappa}B Alternative Pathway in Tumorigenicity

Cancer Research — Wed, 15 Apr 2009 04:00:00 +0100

The nuclear factor-B (NF-B) classic pathway is thought to be critical for tumorigenesis, but little is known about the role of the NF-B alternative pathway in cancer development. Recently, high constitutive nuclear levels of RelB have been observed in human prostate cancer specimens with high Gleason scores. Here, we used four complementary approaches to test whether RelB contributes to tumorigenicity of prostate cancer. Inhibiting RelB in aggressive androgen-independent PC-3 cells by stable or conditional expression of a dominant-negative p100 mutant significantly reduced the incidence and growth rate of tumors. The decrease in tumorigenicity coincided with a reduction in the NF-B target interleukin-8 (IL-8). Consistently, down-regulation of RelB by small interfering RNA targeting also re...

LEF1 in Androgen-Independent Prostate Cancer: Regulation of Androgen Receptor Expression, Prostate Cancer Growth, and Invasion

Cancer Research — Wed, 15 Apr 2009 04:00:00 +0100

In this study, we examined LEF1 expression in androgen-independent cancer as well as its regulation of androgen receptor (AR) expression, prostate cancer growth, and invasion in androgen-independent prostate cancer cells. Affymetrix microarray analysis of LNCaP and LNCaP-AI (androgen-independent variant LNCaP) cells revealed 100-fold increases in LEF1 expression in LNCaP-AI cells. We showed that LEF1 overexpression in LNCaP cells resulted in increased AR expression and consequently enhanced growth and invasion ability, whereas LEF1 knockdown in LNCaP-AI cells decreased AR expression and, subsequently, growth and invasion capacity. Chromatin immunoprecipitation, gel shift, and luciferase assays confirmed LEF1 occupancy and regulation of the AR promoter. Thus, we identified LEF1 as a potenti...

Androgen-Induced Coactivator ANCCA Mediates Specific Androgen Receptor Signaling in Prostate Cancer

Cancer Research — Wed, 15 Apr 2009 04:00:00 +0100

We report here the identification of ANCCA (also known as ATAD2), a new member of the AAA+ ATPase family proteins, as a novel AR coactivator. ANCCA interacts directly with AR and enhances its transcriptional activity, and is required for androgen-stimulated expression of a specific subgroup of genes including IGF1R, IRS-2, SGK1, and survivin. Upon androgen stimulation, ANCCA together with AR is recruited to the specific AR target genes. Suppression of ANCCA expression strongly inhibited the proliferation of androgen-responsive or androgen-independent, AR-positive prostate cancer cells and caused a significant increase of cellular apoptosis. Strikingly, the ANCCA gene itself, located at chromosome 8q24, is highly induced by androgen in androgen-dependent prostate cancer cells and xenograft ...

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The Role of microRNA-221 and microRNA-222 in Androgen-Independent Prostate Cancer Cell Lines

Cancer Research — Wed, 15 Apr 2009 04:00:00 +0100

In conclusion, our data suggest the involvement of miR-221 and miR-222 in the development or maintenance of the CRPC phenotype. [Cancer Res 2009;69(8):3356–63] (Source: Cancer Research)

Atg5 Regulates Phenethyl Isothiocyanate-Induced Autophagic and Apoptotic Cell Death in Human Prostate Cancer Cells

Cancer Research — Wed, 15 Apr 2009 04:00:00 +0100

In conclusion, the present study indicates that Atg5 plays an important role in regulation of PEITC-induced autophagic and apoptotic cell death. [Cancer Res 2009;69(8):3704–12] (Source: Cancer Research)

Change in expression of miR-let7c, miR-100, and miR-218 from high grade localized prostate cancer to metastasis.

Urologic Oncology — Tue, 14 Apr 2009 23:00:00 +0100

CONCLUSION: We hypothesize that miR-let7c, miR-100, and miR-218 may be involved in the process of metastasization of PC, and their role as controllers of the expression of RAS, c-myc, Laminin 5 beta3, THAP2, SMARCA5, and BAZ2A should be matter of additional studies. PMID: 19372056 [PubMed - as supplied by publisher] (Source: Urologic Oncology)

Trial watch: Pivotal oncology trials: outlook for Q2 2009

Nature Reviews Drug Discovery — Tue, 07 Apr 2009 16:48:03 +0100

Trial watch: Pivotal oncology trials: outlook for Q2 2009 Nature Reviews Drug Discovery 8, 266 (2009). doi:10.1038/nrd2861 Author: Ramlah Nehring Data from several pivotal oncology trials that could help drive important treatment advances are due to be reported in the second quarter of 2009. Among these trials, three are particularly notable: sipuleucel-T (Provenge; Dendreon) in androgen-independent prostate cancer (AIPC), bevacizumab (Avastin; Genentech/Roche) in front-line metastatic (Source: Nature Reviews Drug Discovery)

High-resolution array CGH identifies novel regions of genomic alteration in intermediate-risk prostate cancer

The Prostate — Mon, 06 Apr 2009 04:00:00 +0100

Approximately one-third of prostate cancer patients present with intermediate risk disease. Interestingly, while this risk group is clinically well defined, it demonstrates the most significant heterogeneity in PSA-based biochemical outcome. Further, the majority of candidate genes associated with prostate cancer progression have been identified using cell lines, xenograft models, and high-risk androgen-independent or metastatic patient samples. We used a global high-resolution array comparative genomic hybridization (CGH) assay to characterize copy number alterations (CNAs) in intermediate risk prostate cancer. Herein, we show this risk group contains a number of alterations previously associated with high-risk disease: (1) deletions at 21q22.2 (TMPRSS2:ERG), 16q22-24 (containing CDH1), 1...

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Suppression of mutant androgen receptors by flutamide

International Journal of Urology — Mon, 06 Apr 2009 04:00:00 +0100

Conclusions: Flutamide, with its suppressive effects on mutant androgen receptors, may be an alternative to conventional antiandrogens for hormone refractory prostate cancer. (Source: International Journal of Urology)

Characterization of ERG, AR and PTEN Gene Status in Circulating Tumor Cells from Patients with Castration-Resistant Prostate Cancer.

Cell Research — Wed, 01 Apr 2009 04:00:00 +0100

Authors: Attard G, Swennenhuis JF, Olmos D, Reid AH, Vickers E, A'hern R, Levink R, Coumans F, Moreira J, Riisnaes R, Oommen NB, Hawche G, Jameson C, Thompson E, Sipkema R, Carden CP, Parker C, Dearnaley D, Kaye SB, Cooper CS, Molina A, Cox ME, Terstappen LW, de Bono JS Hormone-driven expression of the ERG oncogene after fusion with TMPRSS2 occurs in 30% to 70% of therapy-naive prostate cancers. Its relevance in castration-resistant prostate cancer (CRPC) remains controversial as ERG is not expressed in some TMPRSS2-ERG androgen-independent xenograft models. However, unlike these models, CRPC patients have an increasing prostate-specific antigen, indicating active androgen receptor signaling. Here, we collected blood every month from 89 patients (54 chemotherapy-naive patients and 35 d...

Characterization of ERG, AR and PTEN Gene Status in Circulating Tumor Cells from Patients with Castration-Resistant Prostate Cancer

Cancer Research — Wed, 01 Apr 2009 04:00:00 +0100

Hormone-driven expression of the ERG oncogene after fusion with TMPRSS2 occurs in 30% to 70% of therapy-naive prostate cancers. Its relevance in castration-resistant prostate cancer (CRPC) remains controversial as ERG is not expressed in some TMPRSS2-ERG androgen-independent xenograft models. However, unlike these models, CRPC patients have an increasing prostate-specific antigen, indicating active androgen receptor signaling. Here, we collected blood every month from 89 patients (54 chemotherapy-naive patients and 35 docetaxel-treated patients) treated in phase I/phase II clinical trials of an orally available, highly specific CYP17 inhibitor, abiraterone acetate, that ablates the synthesis of androgens and estrogens that drive TMPRSS2-ERG fusions. We isolated circulating tumor cells (CTC...

Atg5 Regulates Phenethyl Isothiocyanate-Induced Autophagic and Apoptotic Cell Death in Human Prostate Cancer Cells.

Cell Research — Tue, 31 Mar 2009 04:00:00 +0100

In conclusion, the present study indicates that Atg5 plays an important role in regulation of PEITC-induced autophagic and apoptotic cell death. [Cancer Res 2009;69(8):OF1-9]. PMID: 19336571 [PubMed - as supplied by publisher] (Source: Cell Research)

Androgen-Induced Coactivator ANCCA Mediates Specific Androgen Receptor Signaling in Prostate Cancer.

Cell Research — Tue, 24 Mar 2009 04:00:00 +0100

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Proepithelin Encourages Cell Growth And Migration In Prostate Cancer

Cancercompass News: Prostate Cancer — Fri, 20 Mar 2009 09:11:50 +0100

Researchers from Thomas Jefferson University have identified a protein that appears to play a significant role in the growth and migration of prostate cancer cells, especially androgen-independent prostate cancer cells. The study was published in the American Journal of Pathology. They also found that prostate cancer cells express more of the protein when compared to normal prostate cells, according to Andrea Morrione, Ph.D., an associate professor and director of Urology Research for the Kimmel Cancer Center at Jefferson. Dr. Morrione conducted the study with Leonard Gomella, M.D., chairman of the department of Urology, Raffaele Baffa, M.D., an associate professor in the department of Urology, and Renato V. Iozzo, M.D., Ph.D., profes... (Source: Cancercompass News: Prostate Cancer)

Tumoristatic effects of endostatin in prostate cancer is dependent on androgen receptor status

The Prostate — Thu, 19 Mar 2009 04:00:00 +0100

Although anti-angiogenic therapy is a promising new line of therapy for prostate cancer, we recently reported that stable expression of endostatin arrested the progression of prostate cancer to poorly differentiated state and distant metastasis in TRAMP mice. However, the same therapy failed to provide any benefit when given either during or after the onset of metastatic switch. The present study determined the possible mechanisms behind the selective advantage of endostatin therapy in early-stage disease.Angiogenesis-related gene expression analysis was performed to identify target genes and molecular pathways involved in the therapy effects. Based on the results from in vivo studies, and recapitulation of the in vivo data in vitro using tumorigenic and non-tumorigenic human prostate canc...

Androgen-Stimulated UDP-Glucose Dehydrogenase Expression Limits Prostate Androgen Availability without Impacting Hyaluronan Levels

Cancer Research — Tue, 17 Mar 2009 04:00:00 +0100

In this report, we quantified androgen dependence of UGDH, glucuronosyltransferase, and HA synthase expression. Androgen-dependent and androgen-independent human prostate cancer cell lines were used to test the effects of UGDH manipulation on tumor cell growth, HA production, and androgen glucuronidation. Dihydrotestosterone (DHT) increased UGDH expression ~2.5-fold in androgen-dependent cells. However, up-regulation of UGDH did not affect HA synthase expression or enhance HA production. Mass spectrometric analysis showed that DHT was converted to a glucuronide, DHT-G, at a 6-fold higher level in androgen-dependent cells relative to androgen-independent cells. The increased solubilization and elimination of DHT corresponded to slower cellular growth kinetics, which could be reversed in and...

Purine-rich element binding protein (PUR) [alpha] induces endoplasmic reticulum stress response, and cell differentiation pathways in prostate cancer cells

The Prostate — Sun, 08 Mar 2009 05:00:00 +0100

Following androgen ablation treatment for advanced prostate cancer, almost all men relapse after a period of initial response to therapy, which eventually is life threatening. We have previously found that purine-rich element binding protein, PUR[alpha], was significantly repressed in androgen-independent prostate cancer cell lines in comparison to an androgen-dependent line. Moreover, over-expressing PUR[alpha] in androgen-independent prostate cancer cells attenuated their cell proliferation. The aim of the studies described here was to uncover some of the mechanisms by which over-expression of PUR[alpha] attenuates cell proliferation.A set of common genes induced by over-expressing PUR[alpha] both in PC3 and LNCaP cells was analyzed by DNA microarray. The results were then validated util...

Protein Encourages Cell Growth And Migration In Prostate Cancer

ScienceDaily Headlines — Sat, 07 Mar 2009 04:00:00 +0100

Researchers have identified a protein, proepithelin, that appears to play a significant role in the growth and migration of prostate cancer cells, especially androgen-independent prostate cancer cells. (Source: ScienceDaily Headlines)

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Intermittent hormone therapy and its place in the contemporary endocrine treatment of prostate cancer.

Surgical Oncology — Thu, 05 Mar 2009 05:00:00 +0100

Authors: Shaw G, Oliver RT Castration results in dangerous and disabling side effects. Deferred hormone therapy has been shown to be associated with decreased survival. Intermittent hormone therapy (IHT) was attempted initially to reduce morbidity of treating metastatic prostate cancer with stilboestrol. Preclinical work using castrate mice with hormone sensitive prostate tumours demonstrated that pulses of testosterone delayed the onset of androgen independent growth and PSA production in these mice. This led to development of clinical treatment protocols for use in phase II trials by a number of centres in a variety of clinical scenarios. These phase II trials demonstrated apparent safety of this approach, prompting several large scale RCTs. Thus far no difference in survival has bee...

Prostate tumor-initiating cells: A new target for telomerase inhibition therapy?

Biochimica et Biophysica Acta — Mon, 02 Mar 2009 05:00:00 +0100

Authors: Marian CO, Shay JW Conventional therapies for prostate cancer, especially in its androgen-independent form, may result in the survival of small populations of resistant cells with tumor-initiating potential. These "cancer stem cells" are believed to be responsible for cancer relapse, and therapeutic strategies targeting these cells are of great importance. Telomerase is a ribonucleoprotein enzyme responsible for telomere elongation and is activated in the majority of malignancies, including prostate cancer, but is absent in most normal cells. Putative tumor-initiating cells have significant levels of telomerase, indicating that they are an excellent target for telomerase inhibition therapy. In this review, we present some evidence for the hypothesis that conventional therapies...

Solo epothilone yields 21% response rate in androgen-independent prostate cancer

UrologyTimes - Prostate Cancer — Sun, 01 Mar 2009 05:00:00 +0100

First-line treatment with a novel agent known as sagopilone yields a high response rate and substantial decline in PSA in men with androgen-independent prostate cancer, according to findings presented at the European Society for Medical Oncology 33rd Congress. (Source: UrologyTimes - Prostate Cancer)

Knockdown of survivin expression by siRNAs enhances chemosensitivity of prostate cancer cells and attenuates its tumorigenicity.

Acta Biochimica et Biophysica Sinica — Sun, 01 Mar 2009 05:00:00 +0100

Authors: Shen J, Liu J, Long Y, Miao Y, Su M, Zhang Q, Han H, Hao X Survivin, a member of inhibitor of apoptosis family protein, has become an attractive therapeutic target in cancer due to its selective expression in tumor cells and its important roles for tumor cell viability. Here, we show that vector-based small interfering RNAs (siRNAs) silenced survivin expression in prostate cancer cells, resulting in significantly reduced cell proliferation and enhanced apoptosis, and increased the sensitivity of prostate cancer cells (PC-3) to the apoptosis- inducing agent, platinol. Furthermore, PC-3 cells transfected with the siRNA-expressing vector showed lower tumor formation in nude mice xenografts in vivo. These results demonstrated that inhibition of survivin expression by siRNA attenua...

Solo epothilone yields 21% response rate in androgen-independent prostate cancer

UrologyTimes - Prostate Cancer — Sun, 01 Mar 2009 00:00:00 +0100

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Proepithelin Encourages Cell Growth And Migration In Prostate Cancer

Prostate News From Medical News Today — Fri, 27 Feb 2009 10:00:00 +0100

Role of protein kinase C-iota in transformed non-malignant RWPE-1 cells and androgen-independent prostate carcinoma DU-145 cells

Cell Proliferation — Thu, 26 Feb 2009 05:00:00 +0100

Conclusion: Our results suggest that PKC-[iota] is required for cell survival in both transformed non-malignant prostate RWPE-1 cells and androgen-independent malignant prostate DU-145 cells, whereas suppressing PKC-[iota] lead to apoptosis in DU-145 prostate cells. (Source: Cell Proliferation)

Proepithelin encourages cell growth and migration in prostate cancer

EurekAlert! - Cancer — Thu, 26 Feb 2009 05:00:00 +0100

(Thomas Jefferson University) Researchers from Thomas Jefferson University have identified a protein that appears to play a significant role in the growth and migration of prostate cancer cells, especially androgen-independent prostate cancer cells. (Source: EurekAlert! - Cancer)

Global gene expression analysis reveals reduced abundance of putative microRNA targets in human prostate tumours

BMC Genomics - Latest articles — Thu, 26 Feb 2009 05:00:00 +0100

Conclusions: Global gene expression analysis, along with further investigation, suggests that miRNA targets have a significantly reduced transcript abundance in prostate cancer, when compared with the combined pool of all mRNAs. The abnormal expression pattern of miRNA targets in human cancer could be a common feature of the human cancer transcriptome. Our study may help to shed new light on the functional roles of miRNAs in cancer transcriptomics. (Source: BMC Genomics - Latest articles)

Differential Effects of Selenium on Benign and Malignant Prostate Epithelial Cells: Stimulation of LNCaP Cell Growth by Noncytotoxic, Low Selenite Concentrations.

Nutrition and Cancer — Wed, 25 Feb 2009 07:26:04 +0100

We examined the hypothesis that nontoxic concentrations of selenium induce apoptosis and growth inhibition selectively in prostate cancer cells but not in benign prostate cells. Nontumorigenic BPH-1 prostate epithelial cells, androgen-sensitive LNCaP, and androgen-independent PC-3 prostate cancer cells were exposed to sodium selenite at 1 to 10 mu mol/l for 24 to 72 h. Cell proliferation, viability, and apoptosis were assessed by MTT assay, trypan blue exclusion, flow cytometry, DNA laddering, and caspase activation. BPH-1 cells were more sensitive for cytotoxic selenium effects than malignant prostate cells, whereas LNCaP cells were more sensitive than PC-3 cells. At noncytotoxic selenium concentrations, there was no apoptosis in BPH-1 and PC-3 cells and no growth inhibition of LNCaP and ...

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Effects of TRPM8 on the proliferation and motility of prostate cancer PC-3 cells.

Asian Journal of Andrology — Mon, 23 Feb 2009 05:00:00 +0100

Authors: Yang ZH, Wang XH, Wang HP, Hu LQ We investigated the effects of transient receptor potential M8 (TRPM8) channel on the proliferation and motility of androgen-independent prostate cancer PC-3 cells. After being permanently transfected with an empty vector and cDNA encoding the TRPM8 protein, cells were analysed for cell cycle distribution and motility using flow cytometry and scratch assay. Immunocytochemistry and Ca(2+) imaging analysis revealed the overexpression of functional TRPM8 channel on both endoplasmic reticulum and plasma membrane of PC-3-TRPM8 cells. Cell cycle distribution and scratch assay analysis revealed that TRPM8 induced cell cycle arrest at the G(0)/G(1) stage (P < 0.05) and facilitated the cell apoptosis induced by starvation (P < 0.05). Furthermore, ...

Involvement of FLIP in 2-Methoxyestradiol-Induced Tumor Regression in Transgenic Adenocarcinoma of Mouse Prostate Model.

Clinical Cancer Research — Tue, 17 Feb 2009 05:00:00 +0100

CONCLUSION: Targeting Sp1-mediated FLIP signaling pathway may provide a novel approach for prostate cancer management. PMID: 19223508 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)

Low Dose Combinations Of 2-Methoxyestradiol And Docetaxel Block Prostate Cancer Cells In Mitosis And Increase Apoptosis

Cancer / Oncology News From Medical News Today — Wed, 11 Feb 2009 08:00:00 +0100

UroToday.com - Docetaxel (Doc) is the gold standard chemotherapy drug used clinically against androgen-independent prostate cancer (AI-PC) and when combined with prednisone results in a small but significant increase in survival. It is likely other drugs combined with Doc will further increase survival, which is the ultimate goal for treating patients with AI-PC. (Source: Cancer / Oncology News From Medical News Today)

Gene expression of forkhead transcription factors in the normal and diseased human prostate

BJU International — Wed, 11 Feb 2009 05:00:00 +0100

To assess the expression of forkhead transcription factors (FOX) in normal prostate and prostate diseases, as since the first FOX was identified, its family members have been implicated in a variety of cellular processes, including embryonic development and disease. We analysed a set of 12 different FOX genes by quantitative reverse transcription-polymerase chain reaction in prostate zones, prostate cancer, lymph node metastases, benign prostatic hyperplasia (BPH), xenografts and several prostate cell lines. There were striking differences among the expression of various FOX family members; most prominent were the high expression of FOXF1 and FOXF2 in the normal prostate transition zone and BPH, and their decreased expression in prostate cancer. Interestingly, although the FOXF genes are s...

Id-1 expression in androgen-dependent prostate cancer is negatively regulated by androgen through androgen receptor.

Cancer Letters — Fri, 06 Feb 2009 05:00:00 +0100

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Hoxb13 regulatory elements mediate transgene expression during prostate organogenesis and carcinogenesis

Developmental Dynamics — Tue, 03 Feb 2009 05:00:00 +0100

The prostate requires androgens for development and homeostasis. Prostate cancer shares this dependence, however progression to androgen-independence is common after androgen deprivation. There is considerable interest in achieving therapeutic gene expression after androgen ablation using prostate-specific promoters. Paradoxically, known prostate-restricted cis-regulatory elements are androgen dependent. Hoxb13 expression is restricted in adults to the prostate and colon, and robust Hoxb13 expression persists after castration. To locate regulatory elements conferring this expression pattern, a lacZ reporter was inserted into the Hoxb13 locus on a mouse genomic bacterial artificial chromosome. In transgenic mice, this construct recapitulated the Hoxb13 expression pattern, including expressi...

Nuclear versus Cytoplasmic Localization of Filamin A in Prostate Cancer: Immunohistochemical Correlation with Metastases.

Clinical Cancer Research — Sun, 01 Feb 2009 05:00:00 +0100

CONCLUSIONS: The data presented in this study indicate that in prostate cancer, metastasis correlates with cytoplasmic localization of FlnA and may be prevented by cleavage and subsequent nuclear translocation of this protein. PMID: 19188148 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)

Molecular biology of androgen-independent prostate cancer: the role of the androgen receptor pathway

Clinical and Translational Oncology — Thu, 29 Jan 2009 08:16:20 +0100

Abstract Prostate cancer (PC) cells express the androgen receptor (AR) and need the presence of androgens to survive. Androgen suppression is the gold standard first-line therapy for metastatic disease. Almost all PC patients initially respond to hormonal therapy, but most of them gradually develop resistance to castration. There is evidence that these tumours that are considered castration-resistant continue to depend on AR signalling. Several mechanisms that enhance AR signalling in an androgen-depleted environment have been elucidated: (1) AR mutations that allow activation by low androgen levels or by other endogenous steroids, (2) AR amplification and/or overexpression, (3) increased local intracrine synthesis of androgens, (4) changes in AR cofactors and (5) cross-tal...

Proepithelin Regulates Prostate Cancer Cell Biology by Promoting Cell Growth, Migration, and Anchorage-Independent Growth.

Am J Pathol — Thu, 29 Jan 2009 05:00:00 +0100

This study supports the hypothesis that proepithelin may play a critical role as an autocrine growth factor in the establishment and initial progression of prostate cancer. Furthermore, proepithelin may prove to be a useful clinical marker for the diagnosis of prostate tumors. PMID: 19179604 [PubMed - as supplied by publisher] (Source: Am J Pathol)

1,25(OH)2D3 reduces c-Myc expression, inhibiting proliferation and causing G1 accumulation in C4-2 prostate cancer cells.

Endocrinology — Thu, 22 Jan 2009 05:00:00 +0100

Authors: Rohan JN, Weigel NL There is an inverse correlation between exposure to sunlight (the major source of vitamin D) and the risk for prostate cancer, the most common non-cutaneous cancer and second most common cause of death from cancer in American men. The active metabolite of vitamin D, 1,25(OH)2D3 acting through the vitamin D receptor (VDR) decreases prostate cancer cell growth and invasiveness. The precise mechanisms by which 1,25(OH)2D3 inhibits growth in prostate cancer have not been fully elucidated. Treatment with 1,25(OH)2D3 causes an accumulation in the G0/G1 phase of the cell cycle in several prostate cancer cell lines. One potential target known to regulate the G0/G1 to S phase transition is c-Myc, a transcription factor whose overexpression is associated with a numbe...

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Nevirapine restores androgen signaling in hormone-refractory human prostate carcinoma cells both in vitro and in vivo

The Prostate — Fri, 16 Jan 2009 05:00:00 +0100

Prostate carcinomas are androgen-dependent neoplasms which progress toward a hormone-independent phenotype during hormone-deprivation therapy. We evaluated nevirapine, a reverse transcriptase inhibitor, as a new treatment in hormone-refractory prostate carcinoma cells with the aim of restoring the androgen-dependency of tumor cells, the rationale being that endogenous reverse transcriptase is up-regulated in transformed cells and reverse transcriptase inhibitors exert a differentiating activity in human tumors.Nevirapine induced extensive reprogramming of gene expression in vitro with up-regulation of genes that might be silenced during prostate tumor progression (i.e., K18, PSA and androgen receptor) and down-regulation of genes involved in the progression toward an androgen-independent p...

Stromal Anti-Apoptotic Androgen Receptor Target Gene c-FLIP in Prostate Cancer

The Journal of Urology — Sat, 10 Jan 2009 10:02:03 +0100

Conclusions: These results indicate the over expression of stromal c-FLIP and its function for promoting prostate cancer growth and invasion. (Source: The Journal of Urology)

Optimal timing of chemotherapy in androgen independent prostate cancer.

Urologic Oncology — Thu, 01 Jan 2009 05:00:00 +0100

CONCLUSIONS: Currently, docetaxel therapy should be reserved for patients with metastatic AIPC who have progressed despite one or more hormonal therapies. In most patients, more than one hormonal treatment can be offered before chemotherapy is initiated. Studies that test the efficacy of chemotherapy early in the natural history of prostate cancer are under way or are planned. PMID: 19111808 [PubMed - in process] (Source: Urologic Oncology)

Oncogenic activation of androgen receptor.

Urologic Oncology — Thu, 01 Jan 2009 05:00:00 +0100

CONCLUSION: The results showed that AR can be activated by neuropeptide, a ligand for G-protein coupled receptor, in the absence of androgen. The activation goes through Src-tyrosine kinase pathway, and tyrosine kinase inhibitor is a potentially useful adjunctive therapy during androgen ablation. PMID: 19111798 [PubMed - in process] (Source: Urologic Oncology)

Mechanisms mediating androgen receptor reactivation after castration.

Urologic Oncology — Thu, 01 Jan 2009 05:00:00 +0100

Authors: Yuan X, Balk SP Androgen deprivation is still the standard systemic therapy for metastatic prostate cancer (PCa), but patients invariably relapse with a more aggressive form of PCa termed hormone refractory, androgen independent, or castration resistant PCa (CRPC). Significantly, the androgen receptor (AR) is expressed at high levels in most cases of CRPC, and these tumors resume their expression of multiple AR-regulated genes, indicating that AR transcriptional activity becomes reactivated at this stage of the disease. The molecular basis for this AR reactivation remains unclear, but possible mechanisms include increased AR expression, AR mutations that enhance activation by weak androgens and AR antagonists, increased expression of transcriptional coactivator proteins, and a...

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Anti-androgen-independent prostate cancer effects of ginsenoside metabolites In Vitro: Mechanism and possible structure-activity relationship investigation.

Archives of Pharmacal Research — Thu, 01 Jan 2009 05:00:00 +0100

Authors: Li W, Liu Y, Zhang JW, Ai CZ, Xiang N, Liu HX, Yang L Treatment of androgen-independent prostate cancer (AIPC) remains unsatisfactory. In our present experiment, natural occurring ginsenosides (NOGs) and intestinal bacterial metabolites (IBMs) were employed to investigate their anti-AIPC cell growth activity using PC-3 cells. Our results showed that the IBMs exerted more portent anti-AIPC activity than NOGs, by decreasing survival rate, inhibiting proliferation, inducing apoptosis, and leading to cell cycle arrest in AIPC PC-3 cells. The increase of LogP and decrease of C-6 steric hindrance, which were caused by deglycosylation by intestinal bacteria, may be the reason for the higher anti-AIPC activity of IBMs. PMID: 19183876 [PubMed - in process] (Source: Archives of Phar...

Aberrant Activation of Androgen Receptor in a New Neuropeptide-Autocrine Model of Androgen-Insensitive Prostate Cancer

Cancer Research — Wed, 31 Dec 2008 05:00:00 +0100

Treatment of advanced prostate cancer with androgen deprivation therapy inevitably renders the tumors castration-resistant and incurable. Under these conditions, neuroendocrine differentiation of prostate cancer (CaP) cells is often detected and neuropeptides released by these cells may facilitate the development of androgen independence. Exemplified by gastrin-releasing peptide (GRP), these neuropeptides transmit their signals through G protein–coupled receptors, which are often overexpressed in prostate cancer, and aberrantly activate androgen receptor (AR) in the absence of androgen. We developed an autocrine neuropeptide model by overexpressing GRP in LNCaP cells and the resultant cell line, LNCaP-GRP, exhibited androgen-independent growth with enhanced motility in vitro. When or...

Mechanisms of prostate cancer cell survival after inhibition of AR expression

Journal of Cellular Biochemistry — Mon, 29 Dec 2008 05:00:00 +0100

Recent reports have shown that the AR is the key determinant of the molecular changes required for driving prostate cancer cells from an androgen-dependent to an androgen-independent or androgen depletion-independent (ADI) state. Several recent publications suggest that down-regulation of AR expression should therefore be considered the principal strategy for the treatment of ADI prostate cancer. However, no valid data is available about how androgen-dependent prostate cancer cells respond to apoptosis-inducing drugs after knocking down AR expression and whether prostate cancer cells escape apoptosis after inhibition of AR expression. This review will focus on mechanisms of prostate cancer cell survival after inhibition of AR activity mediated either by androgen depletion or by targeting t...

Differential involvement of reactive oxygen species and nucleoside transporters in cytotoxicity induced by two adenosine analogues in human prostate cancer cells

The Prostate — Tue, 23 Dec 2008 05:00:00 +0100

Elevated levels of cellular oxidative stress represent a specific vulnerability of malignant cells and exposure to cytotoxic drugs is known to induce oxidative stress in cancer cells. The effects of two adenosine analogues, 2-chloroadenosine and 2-chlorodeoxyadenosine, were investigated to assess their mechanism of action in prostate cancer cells.Androgen-independent and -sensitive (PC3 and LNCaP) prostate cancer cells and mouse primary prostate cultures were used in the study. Proliferation and cell cycle progression were analyzed in the presence of 2-chloroadenosine and 2-chlorodeoxyadenosine. Adenosine receptors and nucleoside transporters expression were determined by RT-PCR. GSH and reactive oxygen species levels were determined by DTNB and DCFH-DA, respectively. Nuclear translocation...

Butanol fraction containing berberine or related compound from nexrutine® inhibits NF[kappa]B signaling and induces apoptosis in prostate cancer cells

The Prostate — Tue, 23 Dec 2008 05:00:00 +0100

Epidemiological and laboratory studies support the hypothesis that several plant components influence prostate carcinogenesis and holds promise for disease prevention. Previously we reported that Nexrutine® (bark extract from Phellodendron amurense) inhibits proliferation of prostate cancer cells and prostate tumor development in the transgenic adenocarcinoma of mouse prostate (TRAMP) model through modulation of Akt signaling pathway. In the present investigation we conducted studies to further define the mechanism of action of Nexrutine® and to identify the active component associated with its biological activity.Androgen-responsive, androgen-independent human prostate cancer cell lines and tissues from TRAMP mice fed Nexrutine® were used in these studies. Activity guided fractionation...

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Src as a therapeutic target in men with prostate cancer and bone metastases

BJU International — Mon, 22 Dec 2008 05:00:00 +0100

While responsive to androgen ablation in its early stages, prostate cancer eventually becomes castration-resistant and metastasizes preferentially to bone. Once this happens, the disease carries considerable morbidity and is incurable. The process of bone metastasis involves a complex interplay between tumour and bone tissue. The eventual characteristic clinical presentation of disorganized osteoblastic bone lesions is preceded by a facilitatory osteoblastic phase; an osteoblastic component then continues to underlie the process. Increasing evidence has shown a ubiquitous role for Src (a proto-oncogene tyrosine-protein kinase) in multiple tumour and bone-signalling processes involved in prostate tumour progression, driving proliferation, survival, migration and transition to androgen-indep...

Stroma-epithelium crosstalk in prostate cancer.

Asian Journal of Andrology — Mon, 22 Dec 2008 05:00:00 +0100

Authors: Niu YN, Xia SJ The critical role played by stroma-epithelium crosstalk in carcinogenesis and progression of prostate cancer has been increasingly recognized. These interactions are mediated by a variety of paracrine factors secreted by cancer cells and/or stromal cells. In human prostate cancer, reactive stroma is characterized by an increase in myofibroblasts and a corresponding amplification of extracellular matrix production and angiogenesis. Permanent genetic mutations have been reported in stromal cells as well as in tumour cells. Transforming growth factor-beta, vascular endothelial growth factor, platelet-derived growth factor and fibroblast growth factor signalling pathways are involved in the process of angiogenesis, whereas hepatocyte growth factor, insulin-like grow...

A Transcription-Independent Function of FOXO1 in Inhibition of Androgen-Independent Activation of the Androgen Receptor in Prostate Cancer Cells

Cancer Research — Mon, 15 Dec 2008 05:00:00 +0100

Increasing evidence suggests that aberrant activation of the androgen receptor (AR) plays a pivotal role in the development and progression of androgen depletion–independent prostate cancer (PCa) after androgen deprivation therapy. Here, we show that loss of the PTEN tumor suppressor gene is associated with hyperactivation of the AR in human PCa cell lines. This effect is mediated primarily by its downstream effector FOXO1. In addition to the inhibition of androgenic activation of the AR, forced expression of FOXO1 in PTEN-negative PCa cells also inhibits androgen-independent activation of the AR in a manner independent of FOXO1 transcriptional function. In contrast, silencing of FOXO1 in PTEN-positive cells not only increases the basal activity of the AR in the absence of androgens,...

A transcription-independent function of FOXO1 in inhibition of androgen-independent activation of the androgen receptor in prostate cancer cells.

Cell Research — Mon, 15 Dec 2008 05:00:00 +0100

Authors: Liu P, Li S, Gan L, Kao TP, Huang H Increasing evidence suggests that aberrant activation of the androgen receptor (AR) plays a pivotal role in the development and progression of androgen depletion-independent prostate cancer (PCa) after androgen deprivation therapy. Here, we show that loss of the PTEN tumor suppressor gene is associated with hyperactivation of the AR in human PCa cell lines. This effect is mediated primarily by its downstream effector FOXO1. In addition to the inhibition of androgenic activation of the AR, forced expression of FOXO1 in PTEN-negative PCa cells also inhibits androgen-independent activation of the AR in a manner independent of FOXO1 transcriptional function. In contrast, silencing of FOXO1 in PTEN-positive cells not only increases the basal acti...

Combined effects of terazosin and genistein on a metastatic, hormone-independent human prostate cancer cell line.

Cancer Letters — Mon, 15 Dec 2008 05:00:00 +0100

In conclusion, the terazosin/genistein combination was more effective in inhibiting cell growth and VEGF expression as well as inducing apoptosis of the metastatic, androgen-independent prostate cancer cell line, DU-145, than either alone. The doses used in this study are in lower and nontoxic anticancer dosage range, suggesting this combination has potential for therapeutic use. PMID: 19091461 [PubMed - as supplied by publisher] (Source: Cancer Letters)

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Lipido-sterolic extract of Serenoa repens (LSESr, Permixon®) treatment affects human prostate cancer cell membrane organization

Journal of Cellular Physiology — Wed, 10 Dec 2008 05:00:00 +0100

In conclusion, LSESr administration results in complex changes in cell membrane organization and fluidity of prostate cancer cells that have progressed to hormone-independent status. J. Cell. Physiol. © 2008 Wiley-Liss, Inc. (Source: Journal of Cellular Physiology)

Bone-Targeted Therapy: Phase II Study of Strontium-89 in Combination With Alternating Weekly Chemohormonal Therapies for Patients With Advanced Androgen-Independent Prostate Cancer.

American Journal of Clinical Oncology - Current Table Of Contents — Sun, 07 Dec 2008 08:46:29 +0100

Page: 532DOI: 10.1097/COC.0b013e318172aa92Authors: Amato, Robert J. DO; Hernandez-McClain, Joan MPH; Henary, Haby MD (Source: American Journal of Clinical Oncology - Current Table Of Contents)

Implications of insulin-like growth factor-I for prostate cancer therapies

International Journal of Urology — Fri, 05 Dec 2008 05:00:00 +0100

In the last decade, abundant evidence has suggested that the insulin-like growth factor (IGF) family comprises a multi-component network of molecules involved in the regulation of both physiological and pathological growth processes in the prostate. The IGF axis plays an important role in the tumorigenesis and neoplastic growth of prostate cancer. Epidemiological observations indicate that circulating IGF-I levels are positively associated with increased risk of prostate cancer. Activation of IGF-I receptor (IGF-IR) by IGF-I has mitogenic and anti-apoptotic effects on normal and malignant prostate cells. Therapeutic alternatives in men with progressive prostate cancer after androgen ablation are very limited and more effective therapies are needed for such patients. Inactivation of the IGF...

Ionizing Radiation Induces Prostate Cancer Neuroendocrine Differentiation through Interplay of CREB and ATF2: Implications for Disease Progression

Cancer Research — Mon, 01 Dec 2008 05:00:00 +0100

Radiation therapy is a first-line treatment for prostate cancer patients with localized tumors. Although some patients respond well to the treatment, ~10% of low-risk and up to 60% of high-risk prostate cancer patients experience recurrent tumors. However, the molecular mechanisms underlying tumor recurrence remain largely unknown. Here we show that fractionated ionizing radiation (IR) induces differentiation of LNCaP prostate cancer cells into neuroendocrine (NE)-like cells, which are known to be implicated in prostate cancer progression, androgen-independent growth, and poor prognosis. Further analyses revealed that two cyclic AMP–responsive element binding transcription factors, cyclic AMP–response element binding protein (CREB) and activating transcription factor 2 (ATF2), ...

Crosstalk between the Androgen Receptor and {beta}-Catenin in Castrate-Resistant Prostate Cancer

Cancer Research — Mon, 01 Dec 2008 05:00:00 +0100

The androgen-signaling pathway plays an important role in the development and hormonal progression of prostate cancer to the castrate-resistant stage (also called androgen-independent or hormone refractory). The Wnt pathway and β-catenin contribute to prostate biology and pathology. Here application of Affymetrix GeneChip analysis revealed the genomic similarity of the LNCaP hollow fiber model to clinical samples and identified genes with differential expression during hormonal progression. The fiber model samples clustered according to the expression profile of androgen-regulated genes to provide genomic evidence for the reactivation of the AR signaling pathway in castrate-resistant prostate cancer. Pathway-based characterization of gene expression identified activation of the Wnt pa...

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Molecularly targeted radiosensitization of human prostate cancer by modulating inhibitor of apoptosis.

Clinical Cancer Research — Mon, 01 Dec 2008 05:00:00 +0100

CONCLUSIONS: Our results show that small-molecule inhibitors of IAPs can overcome apoptosis resistance and radiosensitize human prostate cancer with high levels of IAPs. Molecular modulation of IAPs may improve the outcome of prostate cancer radiotherapy. PMID: 19047096 [PubMed - in process] (Source: Clinical Cancer Research)

Ionizing Radiation Induces Prostate Cancer Neuroendocrine Differentiation through Interplay of CREB and ATF2: Implications for Disease Progression.

Cell Research — Mon, 01 Dec 2008 05:00:00 +0100

Authors: Deng X, Liu H, Huang J, Cheng L, Keller ET, Parsons SJ, Hu CD Radiation therapy is a first-line treatment for prostate cancer patients with localized tumors. Although some patients respond well to the treatment, approximately 10% of low-risk and up to 60% of high-risk prostate cancer patients experience recurrent tumors. However, the molecular mechanisms underlying tumor recurrence remain largely unknown. Here we show that fractionated ionizing radiation (IR) induces differentiation of LNCaP prostate cancer cells into neuroendocrine (NE)-like cells, which are known to be implicated in prostate cancer progression, androgen-independent growth, and poor prognosis. Further analyses revealed that two cyclic AMP-responsive element binding transcription factors, cyclic AMP-response e...

Apoptotic signaling in bufalin- and cinobufagin-treated androgen-dependent and -independent human prostate cancer cells

Cancer Science — Thu, 27 Nov 2008 05:00:00 +0100

Prostate cancer has its highest incidence in the USA and is becoming a major concern in Asian countries. Bufadienolides are extracts of toxic glands from toads and are used as anticancer agents, mainly on leukemia cells. In the present study, the antiproliferative and apoptotic mechanisms of bufalin and cinobufagin on prostate cancer cells were investigated. Proliferation of LNCaP, DU145, and PC3 cells was measured by 3-(4,5-dimethylthiazol-2-yle)-2,5-diphenyltetrazolium bromide assay and the doubling time (tD) was calculated. Bufalin and cinobufagin caused changes in the tD of three prostate cancer cell lines, which were more significant than that of human mesangial cells. In addition, bufadienolides induced prostate cancer cell apoptosis more significantly than that in breast epithelial ...

Low dose combinations of 2-methoxyestradiol and docetaxel block prostate cancer cells in mitosis and increase apoptosis.

Cancer Letters — Thu, 27 Nov 2008 05:00:00 +0100

Authors: Reiner T, Pozas AD, Gomez LA, Perez-Stable C Clinical trials have shown that chemotherapy with docetaxel (Doc) combined with prednisone can improve survival of patients with androgen-independent prostate cancer (AI-PC). It is likely that the combination of Doc with other novel agents would also improve the survival of AI-PC patients. We investigated whether the combination of Doc and 2-methoxyestradiol (2ME2), an endogenous metabolite of estradiol promising for cancer therapy, can increase apoptotic cell death in prostate cancer cells. Low concentration 2ME2 (0.5-1muM)+Doc (0.05-0.1nM) combinations inhibit cell growth, increase G2/M cell cycle arrest, and increase apoptosis more effectively than the single concentrations in a variety of human AI-PC cells. Effects on apoptosis ...

Investigators At University Of California Target Prostate Cancer

Cancercompass News: Prostate Cancer — Sat, 22 Nov 2008 05:00:00 +0100

"Lymph node involvement denotes a poor outcome for patients with prostate cancer. Our group, along with others, has shown that initial tumor cell dissemination to regional lymph nodes via lymphatics also promotes systemic metastasis in mouse models," scientists in the United States report. "The aim of this study was to investigate the efficacy of suppressive therapies targeting either the angiogenic or lymphangiogenic axis in inhibiting regional lymph node and systemic metastasis in subcutaneous and orthotopic prostate tumor xenografts. Both androgen-dependent and more aggressive androgen-independent prostate tumors were used in our investigations. Interestingly, we observed that the threshold for dissemination is lower in the vascular-r... (Source: Cancercompass News: Prostate Cancer)

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Enhanced expression of bcl-2 following antisense oligonucleotide mediated growth factor deprivation

Medical Oncology — Wed, 19 Nov 2008 18:52:43 +0100

Abstract Although the role of bcl-2 in apoptosis has been described, its involvement in prostate cancer (CAP) progression is less well understood, but thought to be involved with the transition of CAP from androgen-sensitivity to androgen-independence, where its expression is augmented following androgen ablation. For treating these recurrent androgen-independent tumors, following hormone treatment failure, a new tier of therapy based upon growth factor deprivation has been suggested, implemented by antisense oligonucleotides (oligos) directed against mRNA encoding a critical growth regulatory autocrine loop (comprised of transforming growth factor-α (TGF-α) and its binding site, the epidermal growth factor receptor (EGFR). To determine whether oligo-induced growth facto...

Change in Markers of Bone Metabolism with Chemotherapy for Advanced Prostate Cancer: Interleukin-6 Response Is a Potential Early Indicator of Response to Therapy

Journal of Interferon — Mon, 17 Nov 2008 17:07:39 +0100

Journal of Interferon & Cytokine Research , Vol. 0, No. 0. Men with androgen-independent prostate cancer (AIPC) frequently have bone metastasis. The effects of chemotherapy on markers of bone metabolism have not been well characterized. We conducted a prospective study of patients with AIPC randomized in the ... (Source: Journal of Interferon)

Androgen-Regulated And Highly Tumorigenic Human Prostate Cancer Cell Line Established From A Transplantable Primary CWR22 Tumor

Health News from Medical News Today — Sat, 15 Nov 2008 09:00:00 +0100

UroToday.com - The molecular mechanisms underlying development of androgen-independent growth of prostate cancer are largely unknown, and no effective therapies for hormone-refractory prostate cancer exist at present. (Source: Health News from Medical News Today)

The Mitogen-Activated Protein Kinase Phosphatase Vaccinia H1-Related Protein Inhibits Apoptosis in Prostate Cancer Cells and Is Overexpressed in Prostate Cancer

Cancer Research — Fri, 14 Nov 2008 05:00:00 +0100

Androgen ablation during the initial stages of prostate cancer causes regression of the tumor due to an increase in apoptosis and reduced cellular proliferation. However, prostate cancer invariably progresses to an androgen-independent state for poorly understood reasons. Previous studies showed that c-Jun NH2 terminal kinase (JNK) is required for 12-O-tetradecanoylphorbol-13-acetate (TPA)– and thapsigargin (TG)–induced apoptosis in the androgen-responsive prostate cancer cell line LNCaP. Androgens protect LNCaP cells from TPA-induced or TG-induced apoptosis via down-regulation of JNK activation. However, the molecular mechanisms of this inhibition are not clear. Here, we systematically investigated the possible regulation of mitogen-activated protein kinase phosphatases/dual-s...

The interleukin-8 pathway in cancer.

Clinical Cancer Research — Sat, 01 Nov 2008 04:00:00 +0100

Authors: Waugh DJ, Wilson C Interleukin-8 (IL-8) is a proinflammatory CXC chemokine associated with the promotion of neutrophil chemotaxis and degranulation. This chemokine activates multiple intracellular signaling pathways downstream of two cell-surface, G protein-coupled receptors (CXCR1 and CXCR2). Increased expression of IL-8 and/or its receptors has been characterized in cancer cells, endothelial cells, infiltrating neutrophils, and tumor-associated macrophages, suggesting that IL-8 may function as a significant regulatory factor within the tumor microenvironment. The induction of IL-8 signaling activates multiple upstream signaling pathways that (a) impinge on gene expression via regulation of numerous transcription factor activities, (b) modulate the cellular proteome at the le...

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Bicalutamide failure in prostate cancer treatment: Involvement of Multi Drug Resistance proteins.

European Journal of Pharmacology — Wed, 29 Oct 2008 04:00:00 +0100

Authors: Colabufo NA, Pagliarulo V, Berardi F, Contino M, Inglese C, Niso M, Ancona P, Albo G, Pagliarulo A, Perrone R Prolonged bicalutamide treatment induced pathology regression although relapses with a more aggressive form of prostate cancer have been observed. This failure could be due to androgen receptor mutation. In the present work we hypothesized an alternative mechanism responsible for bicalutamide failure involving activity of ATP-binding cassette (ABC) pumps such as P-glycoprotein, Breast Cancer Receptor Protein (BCRP), and Multi Resistant Proteins (MRPs) that extrude the androgen antagonist from the cell membrane. As experimental models androgen-dependent (LnCap) and androgen-independent (PC-3) prostate cancer cell lines have been employed. Bicalutamide has been tested in...

Neuroendocrine differentiation in the progression of prostate cancer

International Journal of Urology — Tue, 28 Oct 2008 04:00:00 +0100

Neuroendocrine (NE) cells originally exist in the normal prostate acini and duct, regulating prostatic growth, differentiation and secretion. Clusters of malignant NE cells are found in most prostate cancer (PCa) cases. NE differentiation (NED) is the basic character of the prostate, either benign or malignant. NE cells hold certain peptide hormones or pro-hormones, which affect the target cells by endocrine, paracrine, autocrine and neuroendocrine transmission in an androgen-independent fashion due to the lack of androgen receptor. NED is accessed by immunohistochemical staining or measurement of serum levels of NE markers. The extent of NED is associated with progression and prognosis of PCa. Chromogranin A (CGA) is the most important NE marker. In metastatic PCa, pretreatment serum CGA ...

Delphinidin, a dietary anthocyanidin in pigmented fruits and vegetables: A new weapon to blunt prostate cancer growth.

Cell Cycle — Sat, 25 Oct 2008 16:01:16 +0100

Authors: Bin Hafeez B, Asim M, Siddiqui IA, Adhami VM, Murtaza I, Mukhtar H In a recent publication, we have shown that delphinidin, an anthocyanidin induces apoptosis and cell cycle arrest in highly metastatic human prostate cancer (PCa) PC3 cells. Extending these studies, we provide additional evidence that delphinidin induces apoptosis and cell cycle arrest in androgen refractory human PCa 22Rnu1 cells and that these effects are concomitant with inhibition of NFkappaB. We observed that delphinidin treatment to 22Rnu1 cells resulted in a dose-dependent (i) G(2)/M phase cell cycle arrest, (ii) induction of apoptosis (iii) and inhibition of NFkappaB signaling. The induction of apoptosis by delphinidin was mediated via activation of caspases since a general caspase inhibitor Z-VAD-FMK s...

Ariad Presents Preclinical Data On Deforolimus And Bicalutamide In Androgen-Independent Prostate Cancer

Cancer / Oncology News From Medical News Today — Fri, 24 Oct 2008 09:00:00 +0100

ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today presented preclinical data on the investigational mTOR inhibitor, deforolimus, alone or in combination with the anti-androgen agent, bicalutamide, in models of prostate cancer. This investigational study shows that the combination inhibits the growth of prostate cancer cell lines in various model systems. (Source: Cancer / Oncology News From Medical News Today)