MedWorm: Androgen Independent Prostate Cancer

MRes/PhD Studentship: The contribution of lysine methylases to androgen receptor function in advanced prostate cancer

Society for Endocrinology — Mon, 06 Feb 2012 12:00:00 +0100

Newcastle University have opened applications for a MRs/PhD studentship in 'The contribution of lysine methylases to androgen receptor function in advanced prostate cancer'. Prostate cancer is the leading cause of cancer-associated deaths in men in the Western world and accounts for approximately 10,000 deaths in the UK. At presentation, prostate cancer growth is androgen-dependent hence the mainstay for treatment is androgen-ablation therapy that block androgen production or action. Unfortunately, after a median time of 18 months, the cancer re-appears in an androgen-independent form, termed castrate-resistant prostate cancer, which is untreatable. This studentship will assess the effectiveness of the lysine methylase proteins in prostate cancer using both in vitro assays and cell line m...

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Remarkable inhibition of mTOR signaling by the combination of rapamycin and 1,4‐phenylenebis(methylene)selenocyanate in human prostate cancer cells

International Journal of Cancer — Sun, 05 Feb 2012 13:03:43 +0100

AbstractPreclinical studies and clinical analyses have implicated the mammalian target of rapamycin (mTOR) pathway in the progression of prostate cancer, suggesting mTOR as a potential target for new therapies. mTOR, a serine/threonine kinase, belongs to two distinct signaling complexes: mTORC1 and mTORC2. We previously showed that the synthetic organoselenium compound, p‐XSC, effectively inhibits viability and critical signaling molecules (e.g., androgen receptor, Akt) in androgen responsive (AR) and androgen independent (AI) human prostate cancer cells. Based on its inhibition of Akt, we hypothesized that p‐XSC modulates mTORC2, an upstream regulator of the kinase. We further hypothesized that combining p‐XSC with rapamycin, an mTORC1 inhibitor, would be an effective combinatory st...

Antagonists of growth hormone-releasing hormone inhibit growth of androgen-independent prostate cancer through inactivation of ERK and Akt kinases [Medical Sciences]

Proceedings of the National Academy of Sciences — Tue, 31 Jan 2012 05:00:00 +0100

The management of castration-resistant prostate cancer (CRPC) presents a clinical challenge because of limitations in efficacy of current therapies. Novel therapeutic strategies for the treatment of CRPC are needed. Antagonists of hypothalamic growth hormone-releasing hormone (GHRH) inhibit growth of various malignancies, including androgen-dependent and independent prostate cancer, by suppressing diverse tumoral growth factors, especially GHRH itself, which acts as a potent autocrine/paracrine growth factor in many tumors. We evaluated the effects of the GHRH antagonist, JMR-132, on PC-3 human androgen-independent prostate cancer cells in vitro and in vivo. JMR-132 suppressed the proliferation of PC-3 cells in vitro in a dose-dependent manner and significantly inhibited growth of PC-3 tum...

Immunohistochemical analysis of gastrin-releasing peptide receptor (GRPR) and possible regulation by estrogen receptor βcx in human prostate carcinoma.

Neoplasma — Thu, 19 Jan 2012 04:30:02 +0100

Authors: Nagasaki S, Nakamura Y, Maekawa T, Akahira J, Miki Y, Suzuki T, Ishidoya S, Arai Y, Sasano H Abstract Gastrin-releasing peptide (GRP) belongs to the family of bombesin-like peptides. GRP was demonstrated to stimulate the proliferation and invasiveness of androgen-independent prostate carcinoma. GRP mediates its action through the membrane-bound receptor, GRP receptor (GRPR), which is characterized by a high-affinity binding for both GRP and bombesin. In human prostate cancer tissue, GRPR mRNA was reported to be detectable in more than 90% but its immunolocalizaition has not been reported. Therefore, in this study we immunolocalized GRPR in 51 human prostate cancer cases and correlated the findings with several clinicopathological parameters in order to beter understand t...

Androgen Deprivation Causes Epithelial-Mesenchymal Transition in the Prostate: Implications for Androgen-Deprivation Therapy

Cancer Research — Mon, 16 Jan 2012 05:00:00 +0100

Androgen deprivation is currently a standard-of-care, first-line therapy for prostate cancer in the United States. Although this regimen effectively regresses androgen-dependent disease, relapse often occurs in an androgen-independent manner and is associated with poor prognosis. Such castration-resistant prostate cancer represents a major clinical challenge, and the mechanisms underlying castration resistance are not fully understood. Epithelial–mesenchymal transition (EMT) is a key developmental process and has also been implicated in cancer metastasis and therapeutic resistance in recent years. However, the factors contributing to EMT in human cancers remain unclear. Here, we show that both normal mouse prostate tissue and human LuCaP35 prostate tumor explants display an EMT as well a...

Chronic hypoxia induces androgen-independent and invasive behavior in LNCaP human prostate cancer cells.

Urologic Oncology — Thu, 05 Jan 2012 05:00:00 +0100

CONCLUSIONS: These results suggested that chronic hypoxia plays an important role in enhancement of malignant potential during androgen-independent CaP progression. PMID: 22226664 [PubMed - as supplied by publisher] (Source: Urologic Oncology)

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[How should hormone therapy for castration-resistant prostate cancer be continued?].

Der Urologe. Ausg. A — Sun, 01 Jan 2012 05:00:00 +0100

Authors: Spahn M, Krebs M Abstract After an average of 18-36 months under androgen suppression therapy by surgical castration, LHRH, and steroidal or non-steroidal antiandrogens, almost all patients with metastatic prostate cancer show PSA progression as a sign of androgen-independent but still androgen-sensitive tumor growth. Our understanding and the treatment of such castration-resistant prostate cancer has changed markedly. The introduction of new drugs like abiraterone and MDV3100 has shown that prostate cancer progression even in the"hormone-refractory" stage is driven by androgen receptor signaling. Based on this information the question of whether androgen deprivation therapy in castration-resistant prostate cancer should be continued or not is still of relevance. This revi...

Diet-Induced Hyperinsulinemia Accelerates Growth of Androgen-Independent PC-3 Cells In Vitro.

Nutrition and Cancer — Thu, 15 Dec 2011 05:00:00 +0100

Authors: Vikram A, Jena G Abstract We investigated the effect of insulin and diet-induced hyperinsulinemia on the growth of the PC-3 cells in vitro and discerned the growth promoting effect of insulin in the androgen-independent cells. Sprague-Dawley rats were kept on a high-fat diet for 4 wk for the induction of insulin resistance and hyperinsulinemia. Insulin alone or serum of the rats kept on either normal-pellet diet or high-fat diet was used to stimulate the serum-starved PC-3 cells growth in culture. S961, a high-affinity insulin-receptor antagonist, was used to confirm the insulin-mediated effects. Significant impairment in the glucose disposal rate and increase in the serum glucose and insulin levels was observed in the high-fat-diet-fed rats. The media supplemented with th...

The antitumor bioactivity of 4-(4-fluorophenyl)amino-5, 6, 7-trimethoxyquinazoline against tumor cells in vitro.

Cell Biology International — Fri, 11 Nov 2011 05:00:00 +0100

Authors: Huang Y, Liu F, Zhao L, Wu H, Liu H Abstract In order to create novel potent and selective anticancer agents, the anticancer activities of 4-(4-fluorophenyl)amino-5,6,7-trimethoxyquinazoline on ten kinds of tumor cells were evaluated by MTT assay. The bioassay results showed that title compound possesses broad spectrum of anticancer activity. The mechanism of action of 4-(4-fluorophenyl)amino-5,6,7-trimethoxyquinazoline against tumor cells was studied in androgen-independent prostate cancer PC-3 cells through microscopic observation, LDH release assay, and Western blot. It was found that title compound executed antitumor activity in a dose-dependent manner with 13±1.43 μM IC50 of 72 h treatment. Microscopic observation and LDH release assay revealed that the compound exe...

Overexpression of Fn14 promotes androgen-independent prostate cancer progression through MMP-9 and correlates with poor treatment outcome

Carcinogenesis — Sun, 30 Oct 2011 04:00:00 +0100

In conclusion, the overexpression of Fn14 may contribute to multiple malignant cellular phenotypes associated with prostate cancer (PCa) progression, in part via MMP-9. TWEAK-Fn14 signaling may be a novel therapeutic target of PCa. (Source: Carcinogenesis)

LCoR Acts as a Novel Androgen Receptor Corepressor [Molecular Bases of Disease]

Journal of Biological Chemistry — Fri, 21 Oct 2011 04:00:00 +0100

The activated androgen receptor (AR) promotes prostate cancer (PCa) growth. AR antagonists repress the AR by recruitment of corepressors. Not much is known about the inactivation of AR by corepressors in the presence of agonists (androgens). Here we show that the corepressor LCoR acts as an androgen-dependent corepressor that represses human PCa growth in vivo. In line with this, progressive decrease of ligand-dependent corepressor expression was observed in the PCa TRAMP mouse model with increasing age. LCoR interacts with AR and is recruited to chromatin in an androgen-induced manner. Unexpectedly, the LXXLL motif of LCoR is dispensable for interaction with the AR. Rather, the data indicate that LCoR interacts with the AR DNA binding domain on DNA. Interestingly, the interaction of LCoR ...

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Inhibition of the Androgen Receptor Activity by Coprinus comatus Substances.

Nutrition and Cancer — Fri, 07 Oct 2011 04:00:00 +0100

This study illustrated the potential of substances from the C. comatus mushroom to serve as natural antiandrogenic modulators for the treatment of prostatic disorders. PMID: 21981678 [PubMed - as supplied by publisher] (Source: Nutrition and Cancer)

Physalins A and B Inhibit Androgen-Independent Prostate Cancer Cell Growth through Activation of Cell Apoptosis and Downregulation of Androgen Receptor Expression.

Biological and Pharmaceutical Bulletin — Wed, 05 Oct 2011 16:55:03 +0100

In this study, we showed that two natural compounds, physalins A and B, both secosteriods from Physalisalkekengi var. franchetii, significantly inhibited the growth of two androgen-independent cell lines CWR22Rv1 and C42B, induced apoptosis via c-Jun N-terminal kinase (JNK) and/or extracellular signal-regulated kinase (ERK) activation, and decreased AR expression. In addition, physalins A and B down-regulated the expression of prostate specific antigen (PSA) in C42B cells which is a target gene of AR. Our results suggest that physalin A and B might be useful agents in preventing the growth of androgen-independent prostate cancer (AI-PCa). PMID: 21963499 [PubMed - in process] (Source: Biological and Pharmaceutical Bulletin)

Thermosensitization and induction of apoptosis or cell-cycle arrest via the MAPK cascade by parthenolide, an NF-κB inhibitor, in human prostate cancer androgen-independent cell lines.

International Journal of Molecular Medicine — Mon, 03 Oct 2011 12:33:03 +0100

Thermosensitization and induction of apoptosis or cell-cycle arrest via the MAPK cascade by parthenolide, an NF-κB inhibitor, in human prostate cancer androgen-independent cell lines. Int J Mol Med. 2011 Dec;28(6):1033-42 Authors: Hayashi S, Koshiba K, Hatashita M, Sato T, Jujo Y, Suzuki R, Tanaka Y, Shioura H Abstract Parthenolide (PTL), a nuclear factor-κB (NF-κB) inhibitor, has a significant thermo-enhancement effect. Modification of thermosensitivity by treatment with PTL prior to hyperthermia was investigated in the human prostate cancer androgen-independent cell lines PC3 and DU145. In addition, we analyzed the mechanisms related to induction of apoptosis or G2/M cell-cycle arrest via the effects of ERK1/2, p38 and SAPK/JNK ...

Androgen-independent molecular imaging vectors to detect castration-resistant and metastatic prostate cancer.

Cell Research — Sat, 01 Oct 2011 04:00:00 +0100

Authors: Jiang ZK, Sato M, Wei LH, Kao C, Wu L Abstract Prostate-specific promoters are frequently employed in gene-mediated molecular imaging and therapeutic vectors to diagnose and treat castration-resistant prostate cancer (CRPC) that emerges from hormone ablation therapy. Many of the conventional prostate-specific promoters rely on the androgen axis to drive gene expression. However, considering the cancer heterogeneity and varying androgen receptor status, we herein evaluated the utility of prostate-specific enhancing sequence (PSES), an androgen-independent promoter in CRPC. The PSES is a fused enhancer derived from the prostate-specific antigen (PSA) and prostate-specific membrane antigen gene regulatory region. We augmented the activity of PSES by the two-step transcription...

Androgen-Independent Molecular Imaging Vectors to Detect Castration-Resistant and Metastatic Prostate Cancer

Cancer Research — Thu, 29 Sep 2011 04:00:00 +0100

Prostate-specific promoters are frequently employed in gene-mediated molecular imaging and therapeutic vectors to diagnose and treat castration-resistant prostate cancer (CRPC) that emerges from hormone ablation therapy. Many of the conventional prostate-specific promoters rely on the androgen axis to drive gene expression. However, considering the cancer heterogeneity and varying androgen receptor status, we herein evaluated the utility of prostate-specific enhancing sequence (PSES), an androgen-independent promoter in CRPC. The PSES is a fused enhancer derived from the prostate-specific antigen (PSA) and prostate-specific membrane antigen gene regulatory region. We augmented the activity of PSES by the two-step transcriptional amplification (TSTA) system to drive the expression of imagin...

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Molecular Alterations during Progression of Prostate Cancer to Androgen Independence [Reviews]

Clinical Chemistry — Wed, 28 Sep 2011 04:00:00 +0100

BACKGROUND: Prostate cancer is the most commonly diagnosed cancer among men in North America and is a leading cause of death. Standard treatments include androgen deprivation therapy, which leads to improved clinical outcomes. However, over time, most tumors become androgen independent and no longer respond to hormonal therapies. Several mechanisms have been implicated in the progression of prostate cancer to androgen independence. CONTENT: Most tumors that have become androgen independent still rely on androgen receptor (AR) signaling. Mechanisms that enhance AR signaling in androgen-depleted conditions include: AR gene amplification, AR mutations, changes in the balance of AR cofactors, increases in steroidogenic precursors, and activation via "outlaw" pathways. Along with AR signaling,...

Researchers develop system that finds prostate cancer metastases earlier

UCLA Newsroom: Health Sciences — Thu, 22 Sep 2011 19:12:41 +0100

This study demonstrated the promising utility of a potent, androgen-independent and prostate cancer-specific expression system in directing gene-based molecular imaging in castration-resistant prostate cancer, even in the context of androgen-deprivation therapy," the researchers said. Prostate cancer is the most common cancer among men in the U.S., and its spread to other organs is the major cause of mortality. This year alone, more than 217,000 American men will be diagnosed with the malignancy. Of those, more than 32,000 will die from their disease. The three-year study was funded by the National Institutes of Health, the Jonsson Cancer Center Foundation and UCLA's Specialist Program of Research Excellence in Prostate Cancer. UCLA's Jonsson Comprehensive Cancer Cente...

On the question of the development of prostate cancer

Journal of Men's Health — Mon, 19 Sep 2011 09:18:50 +0100

After transformation from androgen-independent transitory-proliferation cells, the androgen-dependent pool of transitional cells requires the presence of a physiologically necessary level of testosterone for further development. A decrease in the testosterone level is compensated for both by an increase in aromatase and 5α-reductase activity, and by an increase in the production by cells of peptide growth factors: bFGF and others (Pechersky A. et al., 2003). Natural immunity reactions are initiated by a series of chemical structures, that appear among old, proliferating and malignant cells. Highly-active forms of oxygen and nitrogen, as well as other factors determine the cytolytic (including antineoplastic) action of monocytes, macrophages, neutrophils and cytotoxic T-cells to a signific...

Bortezomib represses HIF-1α protein expression and nuclear accumulation by inhibiting both PI3K/Akt/TOR and MAPK pathways in prostate cancer cells

Journal of Molecular Medicine — Sat, 10 Sep 2011 06:01:58 +0100

In this study, we investigated the effect of bortezomib on the expression, activity and localization of HIF-1α in LNCaP (AD) and PC3 (AI) PCa cells. First, we show that hypoxic upregulation of HIF-1α protein levels and activity involves both the PI3K/Akt/mTOR and p44/42 MAPK pathways. Second, bortezomib inhibits expression of HIF-1α protein under both normoxic and hypoxic conditions, represses HIF-1 transcriptional activity and attenuates the release of vascular endothelial growth factor. These effects correlate with the ability of bortezomib to cause dephosphorylation of phospho-Akt, phospho-p70S6K, and phospho-S6RP, thus inactivating a pathway known to be required for HIF-1α protein expression at the translational level. Furthermore, bortezomib also abrogates p44/42 MAPK phosph...

MicroRNA expression profiles in the progression of prostate cancer-from high-grade prostate intraepithelial neoplasia to metastasis.

Urologic Oncology — Sun, 28 Aug 2011 23:00:00 +0100

CONCLUSION: Through the analysis of 14 miRNAs in 4 groups of prostate lesions, which reproduced the progression of CaP, we showed that there is a global loss of miRNA expression at 2 distinct steps. The first related to the transition between HGPIN and localized invasive carcinoma, and the second associated with the transition from localized to metastatic CaP. The importance of our study is in the identification of possible miRNAs and miRNA-targeted genes involved in the progression of prostate carcinogenesis that may help the development of potential diagnostic or prognostic markers as well as the design of new target therapies. PMID: 21880514 [PubMed - as supplied by publisher] (Source: Urologic Oncology)

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Anti-tumor activity of curcumin against androgen-independent prostate cancer cells via inhibition of NF-κB and AP-1 pathway in vitro

Journal of Huazhong University of Science and Technology -- Medical Sciences -- — Sun, 07 Aug 2011 05:52:11 +0100

Summary The anti-tumor activity of curcumin against androgen-independent prostate cancer cells in vitro and the possible mechanism were investigated. After curcumin treatment, the effect of curcumin on the proliferation of prostate cancer PC-3 cells was assessed by CFSE staining. Flow cytometery (FCM) was performed to analyze the cell cycle and the induction of apoptosis of tumor cells. A luciferase reporter gene assay was used to determine the effects of curcumin on the activities of intracellular NF-κB and AP-1 signaling pathways. The results showed curcumin could effectively inhibit the proliferation of PC-3 cells in vitro (P<0.05). Cells were arrested at G2/M phase. After curcumin treatment, the percentage of apoptotic cells was significantly higher than in control g...

Attenuation of IGF-I receptor signaling inhibits serum-induced proliferation of prostate cancer cells.

Growth Hormone and IGF Research — Tue, 02 Aug 2011 23:00:00 +0100

CONCLUSION: Our observations indicate that the stimulating effect of NHS is completely dependent on IGF-I receptor signaling transduction and that IGF-I stimulates DNA synthesis in prostate cancer cells in strong synergy with other serum factors. We speculate that the role of other serum factors could explain the discrepancy between the results observed in different animal models to study the function of IGF-I in prostate cancer. PMID: 21820343 [PubMed - as supplied by publisher] (Source: Growth Hormone and IGF Research)

Monoacylglycerol Lipase Exerts Dual Control over Endocannabinoid and Fatty Acid Pathways to Support Prostate Cancer.

Chemistry and Biology — Thu, 28 Jul 2011 23:00:00 +0100

Authors: Nomura DK, Lombardi DP, Chang JW, Niessen S, Ward AM, Long JZ, Hoover HH, Cravatt BF Cancer cells couple heightened lipogenesis with lipolysis to produce fatty acid networks that support malignancy. Monoacylglycerol lipase (MAGL) plays a principal role in this process by converting monoglycerides, including the endocannabinoid 2-arachidonoylglycerol (2-AG), to free fatty acids. Here, we show that MAGL is elevated in androgen-independent versus androgen-dependent human prostate cancer cell lines, and that pharmacological or RNA-interference disruption of this enzyme impairs prostate cancer aggressiveness. These effects were partially reversed by treatment with fatty acids or a cannabinoid receptor-1 (CB1) antagonist, and fully reversed by cotreatment with both agents. We furthe...

Anti-cancer effects of novel flavonoid vicenin-2 as a single agent and in synergistic combination with docetaxel in prostate cancer.

Biochemical Pharmacology — Fri, 22 Jul 2011 23:00:00 +0100

In conclusion, our investigations collectively provide strong evidence that VCN-2 is effective against CaP progression along with indicating that VCN-2 and DTL co-administration is more effective than either of the single agents in androgen-independent prostate cancer. PMID: 21803027 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)

Advancing a clinically relevant perspective of the clonal nature of cancer [Medical Sciences]

Proceedings of the National Academy of Sciences — Mon, 18 Jul 2011 23:00:00 +0100

Cancers frequently arise as a result of an acquired genomic instability and the subsequent clonal evolution of neoplastic cells with variable patterns of genetic aberrations. Thus, the presence and behaviors of distinct clonal populations in each patient's tumor may underlie multiple clinical phenotypes in cancers. We applied DNA content-based flow sorting to identify and isolate the nuclei of clonal populations from tumor biopsies, which was coupled with array CGH and targeted resequencing. The results produced high-definition genomic profiles of clonal populations from 40 pancreatic adenocarcinomas and a set of prostate adenocarcinomas, including serial biopsies from a patient who progressed to androgen-independent metastatic disease. The genomes of clonal populations were found to have ...

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Androgen receptor coregulators NOCR1, TIF2, and ARA70 may account for the hydroxyflutamide insensitivity of prostate cancer cells

Irish Journal of Medical Science — Tue, 12 Jul 2011 05:55:18 +0100

Conclusion ARs and associated coregulators play a central role in the flutamide-insensitive transition of prostate cancer cells. Although AR expression does not change during this transition, the change in AR coregulators may be a critical factor in the development of antiandrogen insensitivity Content Type Journal ArticlePages 1-8DOI 10.1007/s11845-011-0714-4Authors Y. Wang, Department of Urology, Tangdu Hospital, Fourth Military Medical University, Xi’an, 710038 Shaanxi, ChinaJ.-Q. Li, Department of Plastic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, 710038 Shaanxi, ChinaC. Shao, Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032 Shaanxi, ChinaC.-H. Shi, Department of Experimental Animals, Fourt...

Organ specific Gst‐pi expression of the metastatic androgen independent prostate cancer cells in nude mice

The Prostate — Sun, 10 Jul 2011 23:00:00 +0100

CONCLUSIONSGst‐pi expression of the prostate cancers are dependent on metastatic site, and that Gst‐pi has an important role in adapting prostate cancer for growth and metastasis involving an alteration of ROS signals. Prostate © 2011 Wiley‐Liss, Inc. (Source: The Prostate)

Positive HER-2 protein expression in circulating prostate cells and micro-metastasis, resistant to androgen blockage but not diethylstilbestrol

Indian Journal of Urology — Thu, 07 Jul 2011 23:00:00 +0100

Conclusions : The results suggest that HER-2 positive cells are resistant to androgen blockade. In an environment lacking androgens, HER-2 positive cells are selected and survive, while HER-2 negative cells are eliminated thus decreasing the serum PSA. The population of HER-2 positive cells proliferate producing androgen-independent disease. DES does not increase HER-2 expression possibly by stimulating beta-estrogen receptors and blocking HER-2 androgen receptor activation. (Source: Indian Journal of Urology)

The dietary flavonol fisetin enhances the apoptosis-inducing potential of TRAIL in prostate cancer cells.

International Journal of Oncology — Tue, 05 Jul 2011 23:00:00 +0100

This study was designed to investigate the effect of fisetin on the TRAIL-induced apoptosis potential in prostate cancer cells. Prostate cancer cell lines represent an ideal model for research in chemoprevention. Cytotoxicity was measured by MTT and LDH assays. Apoptosis was detected using Αnnexin V-FITC by flow cytometry and fluorescence microscopy. Mito-chondrial membrane potential (ΔΨm) was evaluated using DePsipher staining by fluorescence microscopy. Death receptor (TRAIL-R1 and TRAIL-R2) expression was analysed by flow cytometry. Inhibition of NF-κB (p65) activation was confirmed with an ELISA-based TransAM NF-κB kit. Caspase-8 and caspase-3 activities were determined by colorimetric protease assays. Our study demonstrates that fisetin sensitizes the TRAIL-resistant androgen-de...

The Culinary-Medicinal Mushroom Coprinus comatus as a Natural Antiandrogenic Modulator

Integrative Cancer Therapies — Mon, 27 Jun 2011 23:00:00 +0100

This study illustrates the potential of the C comatus mushroom as a natural antiandrogenic modulator that could serve in the treatment of prostatic diseases. (Source: Integrative Cancer Therapies)

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Comparative biodistribution of imaging agents for in vivo molecular profiling of disseminated prostate cancer in mice bearing prostate cancer xenografts: focus on 111In- and 125I-labeled anti-HER2 humanized monoclonal trastuzumab and ABY-025 Affibody

Nuclear Medicine and Biology — Thu, 23 Jun 2011 04:00:00 +0100

Conclusions: Radiolabeled ABY-025 Affibody molecule provides higher contrast in imaging of HER2-expressing PC xenografts than radiolabeled trastuzumab. Residualizing radiometal label for ABY-025 provides better contrast in imaging of HER2-expressing PC xenografts than nonresidualizing radiohalogen. (Source: Nuclear Medicine and Biology)

Plasma membrane-associated sialidase (NEU3) regulates progression of prostate cancer to androgen-independent growth through modulation of androgen receptor signaling

Cell Death and Differentiation — Thu, 16 Jun 2011 23:00:00 +0100

Authors: S Kawamura, I Sato, T Wada, K Yamaguchi, Y Li, D Li, X Zhao, S Ueno, H Aoki, T Tochigi, M Kuwahara, T Kitamura, K Takahashi, S Moriya & T Miyagi (Source: Cell Death and Differentiation)

Antitumor effect of meclofenamic acid on human androgen-independent prostate cancer: a preclinical evaluation

International Urology and Nephrology — Fri, 10 Jun 2011 06:32:08 +0100

Conclusions Meclofenamic acid was shown to be a potential antineoplastic agent for both androgen-dependent and androgen-independent prostate cancer. Content Type Journal ArticlePages 1-7DOI 10.1007/s11255-011-0012-0Authors Alejandro D. Soriano-Hernández, School of Medicine, University of Colima., Av. Universidad 333, Colonia Las Víboras, 28040 Colima, Col., MexicoHector R. Galvan-Salazar, School of Medicine, University of Colima., Av. Universidad 333, Colonia Las Víboras, 28040 Colima, Col., MexicoDaniel A. Montes-Galindo, School of Medicine, University of Colima., Av. Universidad 333, Colonia Las Víboras, 28040 Colima, Col., MexicoAlejandrina Rodriguez-Hernandez, School of Medicine, University of Colima., Av. Universidad 333, Colonia Las Víboras, 28040 Colima, ...

Omega-3 Fatty Acid Inhibition of Prostate Cancer Progression to Hormone Independence Is Associated With Suppression of mTOR Signaling and Androgen Receptor Expression.

Nutrition and Cancer — Thu, 09 Jun 2011 23:00:00 +0100

Authors: Friedrichs W, Ruparel SB, Marciniak RA, Degraffenried L Currently, progression of prostate cancer to androgen independence remains the primary obstacle to improved survival. In order to improve overall survival, novel treatment strategies that are based upon specific molecular mechanisms that prolong the androgen-dependent state and that are useful for androgen-independent disease need to be identified. Both epidemiological as well as preclinical data suggest that omega-3 fatty acids are effective primary tumor prevention agents; however, their efficacy at preventing and treating refractory prostate cancer has not been as thoroughly investigated. We used an in vitro model of androgen ablation to determine the effect of treatment with omega-3 fatty acids on the progression to a...

Androgen‐independent Effects of Serenoa repens Extract (Prostasan®) on Prostatic Epithelial Cell Proliferation and Inflammation

Phytotherapy Research — Tue, 07 Jun 2011 23:00:00 +0100

Extracts from Serenoa repens are widely used for the treatment of benign prostatic hyperplasia (BPH) and traditionally for prostatitis. In the present study we evaluated the biological effects of Serenoa repens extract (Prostasan®) on prostate cells beyond its known antiandrogenic actions. Prostasan® inhibited epidermal growth factor (EGF) and lipopolysaccharide (LPS) induced proliferation of the prostatic epithelial, androgen independent cell line PC‐3. At effective concentrations of 50 µg/mL, Prostasan® partly displaced EGF from EGF receptor (EGFR) but fully blocked EGF‐induced cell proliferation of PC‐3 cells. Similarly, Prostasan® inhibited LPS‐induced proliferation of PC‐3 cells without affecting LPS activation of the NFĸB pathway via toll‐like receptor‐4 (TLR‐...

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Phase III study compares docetaxel plus high-dose calcitriol to docetaxel plus prednisone for castration-resistant prostate cancer

NeLM - News — Mon, 30 May 2011 23:00:00 +0100

Source: Journal of Clinical Oncology Area: News According to the findings from the ASCENT-2 study, the use of DN-101 (high-dose calcitriol) in combination with docetaxel may worsen the overall survival of men with castration-resistant prostate cancer (CRPC), compared to the current standard of care. The authors note that docetaxel plus prednisone is the standard first-line treatment for progressive CRPC; however more effective combinations are an unmet need. A Phase II study of DN-101 - a novel high-concentration formulation of calcitriol - found that its addition to docetaxel improved some secondary endpoints versus placebo in this patient population. The purpose of the current multicentre Phase III study was to evaluate this combination further. &nbs...

Randomized, Open-Label Phase III Trial of Docetaxel Plus High-Dose Calcitriol Versus Docetaxel Plus Prednisone for Patients With Castration-Resistant Prostate Cancer [Urologic Oncology]

Journal of Clinical Oncology — Thu, 26 May 2011 23:00:00 +0100

Conclusion ASCENT treatment was associated with shorter survival than the control. This difference might be due to either weekly docetaxel dosing, which, in a prior study, showed a trend toward inferior survival compared with an every-3-weeks regimen, or DN-101 therapy. (Source: Journal of Clinical Oncology)

Comrad: detection of expressed rearrangements by integrated analysis of RNA-Seq and low coverage genome sequence data

Bioinformatics — Tue, 24 May 2011 23:00:00 +0100

Motivation: Comrad is a novel algorithmic framework for the integrated analysis of RNA-Seq and whole genome shotgun sequencing (WGSS) data for the purposes of discovering genomic rearrangements and aberrant transcripts. The Comrad framework leverages the advantages of both RNA-Seq and WGSS data, providing accurate classification of rearrangements as expressed or not expressed and accurate classification of the genomic or non-genomic origin of aberrant transcripts. A major benefit of Comrad is its ability to accurately identify aberrant transcripts and associated rearrangements using low coverage genome data. As a result, a Comrad analysis can be performed at a cost comparable to that of two RNA-Seq experiments, significantly lower than an analysis requiring high coverage genome data. Resul...

Natura-Alpha Targets Forkhead Box M1 and Inhibits Androgen-Dependent and -Independent Prostate Cancer Growth and Invasion.

Clinical Cancer Research — Sun, 22 May 2011 23:00:00 +0100

CONCLUSIONS: Natura-alpha could serve as a novel and effective therapeutic agent for treatment of both hormone sensitive and hormone refractory prostate cancer with minimal side effects. PMID: 21606178 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)

Inverse baseline expression pattern of the NEP/neuropeptides and NFkappaB/proteasome pathways in androgen-dependent and androgen-independent prostate cancer cells

Cancer Cell International — Sat, 14 May 2011 23:00:00 +0100

Conclusions: Our results seem to support evidence for divergent patterns of expression of the NFkappaB/proteasome pathway with relation to components of the NEP/neuropeptide axis in PC cells of different level of androgen dependence. NEP and ET-1 are inversely and directly related to an activated state of the NFkappaB/proteasome pathway, respectively. A combination therapy targeting both pathways may ultimately prove to be of benefit in clinical practice. (Source: Cancer Cell International)

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Troglitazone suppresses c-Myc levels in human prostate cancer cells via a PPARγ-independent mechanism.

Cancer Biology and Therapy — Fri, 13 May 2011 17:01:28 +0100

Authors: Akinyeke TO, Stewart LV Troglitazone is a ligand for the peroxisome proliferator activated receptor gamma (PPARγ) that decreases growth of human prostate cancer cells in vitro and in vivo. However, the mechanism by which troglitazone reduces prostate cancer cell growth is not fully understood. To understand the signaling pathways involved in troglitazone-induced decreases in prostate cancer growth, we examined the effect of troglitazone on androgen-independent C4-2 human prostate cancer cells. Initial experiments revealed troglitazone inhibited C4-2 cell proliferation by arresting cells in the G0/G1 phase of the cell cycle and inducing apoptosis. Since the proto-oncogene product c-Myc regulates both apoptosis and cell cycle progression, we next examined whether troglitazone a...

Characterization of bone metastases from rapid autopsies of prostate cancer patients.

Clinical Cancer Research — Sun, 08 May 2011 23:00:00 +0100

CONCLUSION: This represents a versatile and practical approach that may be employed to characterize the steps in metastasis and the phenotypic characteristics of osseous metastasis of prostate cancer and to profile RNA, DNA and cDNA from tumor samples metastatic to the bone. PMID: 21555375 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)

MDM2 antagonists boost antitumor effect of androgen withdrawal: Implications for therapy of prostate cancer

BioMed Central — Mon, 02 May 2011 23:00:00 +0100

Conclusions: Since majority of prostate tumors express wild-type p53, its activation by MDM2 antagonists in combination with androgen depletion may offer an efficacious new approach to prostate cancer therapy. (Source: BioMed Central)

Benzyldihydroxyoctenone, a novel nonsteroidal antiandrogen, shows differential apoptotic induction in prostate cancer cells in response to their androgen responsiveness.

Journal of Microbiology and Biotechnology — Sat, 30 Apr 2011 23:00:00 +0100

Authors: Suh H, Oh HL, Lee CH The molecular mechanisms of apoptotic induction by benzyldihydroxyoctenone (BDH), a nonsteroidal antiandrogen, isolated from the culture broth of Streptomyces sp., have been previously published in prostate cancer LNCaP cells. Apoptotic induction of BDH-treated LNCaP cells was associated with downregulation of Bcl-xL that caused, in turn, cytochrome c release from mitochondria, and activation of procaspases and specific proteolytic cleavage of poly(ADP-ribose) polymerase (PARP). The purpose of the present study was to investigate the patterns of apoptotic induction by BDH in non-prostate, ovarian cancer PA-1 (androgen-independent and -insensitive) cells and prostate cancer cells with different androgen responsiveness, such as C4-2 (androgen-independent and...

The significance of Her2 on androgen receptor protein stability in the transition of androgen requirement in prostate cancer cells

AJP: Endocrinology and Metabolism — Mon, 25 Apr 2011 23:00:00 +0100

Androgen ablation therapy is the most common strategy for suppressing prostate cancer progression; however, tumor cells eventually escape androgen dependence and progress to an androgen-independent phase. The androgen receptor (AR) plays a pivotal role in this transition. To address this transition mystery in prostate cancer, we established an androgen-independent prostate cancer cell line (LNCaPdcc), by long-term screening of LNCaP cells in androgen-deprived conditions, to investigate changes of molecular mechanisms before and after androgen withdrawal. We found that LNCaPdcc cells displayed a neuroendocrine morphology, less aggressive growth, and lower expression levels of cell cycle-related factors, although the cell cycle distribution was similar to parental LNCaP cells. Notably, highe...

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Active sonic hedgehog signaling between androgen independent human prostate cancer cells and normal/benign but not cancer‐associated prostate stromal cells

The Prostate — Sun, 24 Apr 2011 23:00:00 +0100

CONCLUSIONSBased on co‐culture and chimeric tumor models, active Shh‐mediated signaling was demonstrated between AI prostate cancer and NPF in a paracrine‐ and tumor progression‐dependent manner. Our study suggests that drugs like cyclopamine that interfere with Shh signaling could be beneficial in preventing AI progression in prostate cancer cells. Prostate © 2011 Wiley‐Liss, Inc. (Source: The Prostate)

Ursolic acid inhibits multiple cell survival pathways leading to suppression of growth of prostate cancer xenograft in nude mice

Journal of Molecular Medicine — Tue, 05 Apr 2011 09:58:29 +0100

In this study, we investigated the effect of ursolic acid (UA) on NF-κB and STAT3 signaling pathways in both androgen-independent (DU145) and androgen-dependent (LNCaP) prostate cancer cell lines and also prospectively tested the hypothesis of NF-κB and STAT3 inhibition using a virtual predictive functional proteomics tumor pathway technology platform. We found that UA inhibited constitutive and TNF-α-induced activation of NF-κB in DU145 and LNCaP cells in a dose-dependent manner. The suppression was mediated through the inhibition of constitutive and TNF-α-induced IκB kinase (IKK) activation, phosphorylation of IκBα and p65 and NF-κB-dependent reporter activity. Furthermore, UA suppressed both constitutive and inducible STAT3 activation in prostate cancer cells concomitant ...

Detection of MicroRNAs in Prostate Cancer Cells by MicroRNA Array

Springer protocols feed by Cell Biology — Fri, 01 Apr 2011 13:32:34 +0100

MicroRNAs (miRNAs) are a novel class of small noncoding RNAs that regulate gene expression at the posttranscriptional level and play a critical role in many important biological processes and pathological development. In the past few years, miRNAs have been implicated to play an important role in cancer initiation and development. In this chapter, we describe a protocol for the analysis and characterization of miRNAs in prostate cancer cells using a simple but effective array platform. The array is composed of 553 nonredundant miRNAs encompassing the entire set of known miRNAs in humans and mice. As an example, profiling of miRNAs in four prostate cancer cell lines has revealed that a set of miRNAs were differentially expressed between androgen-dependent and androgen-independent metastatic...

Prostate-specific antigen kallikrein and non-ST elevation myocardial infarction

International Journal of Cardiology — Tue, 29 Mar 2011 23:00:00 +0100

I greatly appreciated the letter to the Editor by Dominguez-Rodriguez A, Abreu-Gonzalez P, Avanzas P, Hernandez-Garcia C, Carrillo-Perez Tome M, Lara-Padron A. “Prostate-specific antigen kallikrein is not a marker of non-ST elevation acute coronary syndrome.” regarding "Prostate-specific antigen kallikrein and acute myocardial infarction: where we are. Where are we going?" . Their letter focused on the difficulties on the interpretation of the role of the prostate-specific antigen kallikrein (PSA) regarding cardiovascular system and particularly regarding acute coronary syndromes. Increasing evidence suggests that PSA relates to the cardiovascular system . Of note, increased PSA serum levels have been reported after prolonged cardiopulmonary resuscitation , cardiac surgery , extracorpo...

Analyzing Serum-Stimulated Prostate Cancer Cell Lines After Low-Fat, High-Fiber Diet and Exercise Intervention

International Journal of Telemedicine and Applications — Tue, 15 Mar 2011 14:53:10 +0100

Serum from men undergoing a low-fat, high-fiber diet and exercise intervention has previously been shown to decrease growth and increase apoptosis in serum-stimulated, androgen-dependent LNCaP cells associated with a reduction in serum IGF-I. Here we sought to determine the underlying mechanisms for these anticancer effects. Again, the intervention slowed growth and increased apoptosis in LNCaP cells; responses that were eliminated when IGF-I was added back to the post-intervention samples. The p53 protein content was increased and NFκB activation reduced in the post serum-stimulated LNCaP cells. Similar results were observed when the IGF-I receptor was blocked in the pre-intervention serum. In androgen-independent PC-3 cells, growth was reduced while none of the other factors were...

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PrLZ Protects Prostate Cancer Cells from Apoptosis Induced by Androgen Deprivation via the Activation of Stat3/Bcl-2 Pathway

Cancer Research — Mon, 14 Mar 2011 00:00:00 +0100

In this study, we showed that PrLZ enhanced in vitro growth and colony formation of prostate cancer cells on androgen deprivation as well as tumorigenicity in castrated nude mice. In addition, PrLZ stabilized mitochondrial transmembrane potential, prevented release of cytochrome c from mitochondria to cytoplasm, and inhibited intrinsic apoptosis induced by androgen depletion. Mechanistically, PrLZ elevated the phosphorylation of Akt and Stat3 and upregulated Bcl-2 expression. Our data indicate that PrLZ protects prostate cancer cells from apoptosis and promotes tumor progression following androgen deprivation. In summary, we propose that PrLZ is a novel antiapoptotic gene that is specifically activated in prostate cancer cells escaping androgen deprivation may offer an appealing therapeuti...

TMPRSS2/ERG fusion gene expression alters chemo‐ and radio‐responsiveness in cell culture models of androgen independent prostate cancer

The Prostate — Thu, 10 Mar 2011 00:00:00 +0100

CONCLUSIONSThe effect of TMPRSS2/ERG gene fusions had differing effects on radiosensitivity and chemosensitivity depending on cell line and fusion type. Further work is needed with clinical samples to establish whether TMPRSS2/ERG gene fusions affect radio‐ and chemosensitivity in vivo. Prostate © 2011 Wiley‐Liss, Inc. (Source: The Prostate)

The significance of Her2 on androgen receptor protein stability in the transition of androgen requirement in prostate cancer cells.

American Journal of Physiology. Endocrinology and Metabolism — Tue, 01 Mar 2011 00:00:00 +0100

Authors: Hsu FN, Yang MS, Lin E, Tseng CF, Lin H Androgen ablation therapy is the most common strategy to suppress prostate cancer progression; however, tumor cells eventually escape androgen dependence and progress to an androgen-independent phase. The androgen receptor (AR) plays a pivotal role in this transition. To address this transition mystery in prostate cancer, we established an androgen-independent prostate cancer cell line (LNCaPdcc), by long-term screening of LNCaP cells in androgen-deprived conditions, to investigate changes of molecular mechanisms before and after androgen withdrawal. We found that LNCaPdcc cells displayed a neuroendocrine morphology, less aggressive growth, and lower expression levels of cell cycle-related factors, although the cell cycle distribution wa...

619 activated fibroblast growth factor-inducible 14 (fn14) promotes invasion, migration and proliferation of androgen independent prostate cancer cells through matrix metalloproteinase 9 and correlates with poor treatment outcome

European Urology Supplements — Tue, 01 Mar 2011 00:00:00 +0100

(Source: European Urology Supplements)

829 androgen deprivation selects for androgen independent, tumor-reinitiating cells in models of androgen dependent prostate cancer

European Urology Supplements — Tue, 01 Mar 2011 00:00:00 +0100

(Source: European Urology Supplements)

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Methods for Evaluation of Structural and Biological Properties of Antiinvasive Natural Products

Springer protocols feed by Pharmacology/Toxicology — Thu, 24 Feb 2011 16:43:14 +0100

Prostate cancer is considered the most common cancer form among males in Western countries. Very limited options are available for the treatment of advanced metastatic prostate cancer. More than 50% of today’s anticancer drugs are natural products or derived from a natural origin. To discover new entities with potential to treat prostate cancer at androgen-refractory stages, 36 structurally diverse natural products were screened using functional-based assays. The tested compounds were selected broadly from major secondary metabolites of plants, marine invertebrates, and fungi. These diverse entities were prescreened for their antiinvasive ability against prostate cancer cells, PC-3M, using spheroid disaggregation assay. Active representatives including three selected structural class...

Hormone Depletion-Insensitivity of Prostate Cancer Cells Is Supported by the AR Without Binding to Classical Response Elements.

Genomics Proteomics ... — Thu, 17 Feb 2011 00:00:00 +0100

We examined the importance of AR binding to DNA in prostate cancer cells in which proliferation in the absence of hormone was profoundly (~90%) dependent on endogenous AR and where the receptor was not up-regulated or mutated but was predominantly nuclear. Here, ARE-mediated promoter activation and the binding of AR to a known ARE in the chromatin remained entirely androgen dependent, and the cells showed an androgen-responsive gene expression profile with an unaltered sensitivity to androgen dose. In the same cells, a different set of genes primarily enriched for cell division functions was activated by AR independently of hormone and significantly overlapped the signature gene overexpression profile of hormone ablation-insensitive clinical tumors. After knockdown of endogenous AR, hormon...

Alpha- versus Beta-Particle Radiopeptide Therapy in a Human Prostate Cancer Model (213Bi-DOTA-PESIN and 213Bi-AMBA versus177Lu-DOTA-PESIN)

Cancer Research — Tue, 01 Feb 2011 00:00:00 +0100

In this study, two novel 213Bi-labeled peptides, DOTA-PEG4-bombesin (DOTA-PESIN) and DO3A-CH2CO-8-aminooctanoyl-Q-W-A-V-G-H-L-M-NH2 (AMBA), were compared with 177Lu (β-emitter)-labeled DOTA-PESIN in a human androgen-independent prostate carcinoma xenograft model (PC-3 tumor). Animals were injected with 177Lu-DOTA-PESIN, 213Bi-DOTA-PESIN, or 213Bi-AMBA to determine the maximum tolerated dose (MTD), biodistribution, and dosimetry of each agent; controls were left untreated or were given nonradioactive 175Lu-DOTA-PESIN. The MTD of 213Bi-DOTA-PESIN and 213Bi-AMBA was 25 MBq (0.68 mCi) whereas 177Lu-DOTA-PESIN showed an MTD of 112 MBq (3 mCi). At these dose levels, 213Bi-DOTA-PESIN and 213Bi-AMBA were significantly more effective than 177Lu-DOTA-PESIN. At the same time, 177Lu-DOTA-PESIN sh...

Oncolytic Targeting of Androgen-sensitive Prostate Tumor by the Respiratory Syncytial Virus (RSV): Consequences of Deficient Interferon-dependent Antiviral Defense

BioMed Central — Fri, 28 Jan 2011 00:00:00 +0100

Conclusions: We demonstrated that RSV is potentially a useful therapeutic tool in the treatment of androgen-sensitive and androgen-independent prostate cancer. Moreover, impaired IFN-mediated antiviral response is the likely cause of higher viral burden and resulting oncolysis of androgen-sensitive prostate cancer cells. (Source: BioMed Central)

Use of Abiraterone for Prostate Cancer

The Journal of Urology — Tue, 18 Jan 2011 00:00:00 +0100

Until recently clinicians and translational scientists assumed that medical or surgical castration produced castrate circulating levels of testosterone which were reflected in prostate cancer and its metastasis. This assumption was logical since almost all prostate cancers respond to androgen deprivation therapy. Furthermore, prostate cancer cells were thought to exist as androgen dependent cells that died by apoptosis during androgen deprivation therapy, androgen sensitive cells that became quiescent during androgen deprivation therapy and would repopulate the tumor upon androgen restoration, and androgen independent cells that grew regardless of the availability of androgens. The extent of response to androgen deprivation therapy and the duration of that response were dependent on the re...

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Synthesis and cytotoxic activities of some 2-Arylnaphtho[2,3-d]oxazole-4,9-dione derivatives on androgen-dependent (LNCaP) and androgen-independent (PC3) human prostate cancer cell lines

Investigational New Drugs — Mon, 17 Jan 2011 20:16:02 +0100

Summary The synthesis of five 2-arylnaphtho[2,3-d]oxazole-4,9-dione derivatives was accomplished by refluxing 2-amino-3-bromo-1,4-naphthoquinone with appropriate benzoyl chloride analogs at elevated temperatures. In vitro anticancer evaluation of these compounds was performed on androgen-dependent, LNCaP, and androgen-independent, PC3, human prostate cancer cell lines. In general, these compounds displayed slightly stronger cytotoxicity on the androgen-dependent LNCaP than on the androgen-independent PC3 prostate cancer cell lines. The meta-substituted 2-(3-Chloro-phenyl)-naphtho[2,3-d]oxazole-4,9-dione (10) appear to display the best cytotoxicity on both cell lines with an IC50 of 0.03 μM on LNCaP and 0.08 μM on PC3 after 5 days of exposure. Figur...

Anti-proliferative potential of curcumin in androgen-dependent prostate cancer cells occurs through modulation of the Wingless signaling pathway.

International Journal of Oncology — Fri, 14 Jan 2011 00:00:00 +0100

We report here that the chemopreventive agent curcumin from the rhizome of Curcuma longa was able to affect cell proliferation of androgen-dependent prostate cancer through the induction of cell cycle arrest in G2 and modulation of Wnt signaling. Curcumin decreases the level of Tcf-4, CBP and p300 proteins implicated in the Wnt transcriptional complex that leads to the decrease of ß-catenin/Tcf-4 transcriptional activity and of the expression of ß-catenin target genes (cyclin D1 and c-myc). Subsequent cell death induction is linked to autophagy. Interestingly, in androgen-independent prostate cancer cells, curcumin does not affect Wnt/ß-catenin transcriptional activity. Altogether our results suggest that curcumin is an interesting chemopreventive agent for early stage prostate cancer. ...

MicroRNA-616 Induces Androgen-Independent Growth of Prostate Cancer Cells by Suppressing Expression of Tissue Factor Pathway Inhibitor TFPI-2

Cancer Research — Thu, 13 Jan 2011 00:00:00 +0100

In this study, we report a functional impact in prostate cancer cells for overexpression of the microRNA miR-616, which occurred consistently in cells that were androgen-independent (AI) versus androgen-dependent (AD). miR-616 overexpression was confirmed in malignant prostate tissues as opposed to benign prostate specimens. Stable miR-616 overexpression in LNCaP cells by a lentiviral-based approach stimulated AI prostate cancer cell proliferation in vitro whereas concomitantly reducing androgen-induced cell growth. More importantly, miR-616 overexpressing LNCaP cells overcame castration resistance as shown by an enhanced ability to proliferate in vivo after bilateral orchiectomy. Conversely, antagonizing miR-616 in AI prostate cancer cells yielded opposite effects. Microarray profiling an...

Lycopene and Apo-12'-Lycopenal Reduce Cell Proliferation and Alter Cell Cycle Progression in Human Prostate Cancer Cells.

Nutrition and Cancer — Mon, 03 Jan 2011 00:00:00 +0100

Authors: Ford NA, Elsen AC, Zuniga K, Lindshield BL, Erdman JW Lycopene is associated with a reduced risk of prostate cancer. However, lycopene may not be wholly responsible for the effects seen in vivo or in cell culture systems. Apo-lycopenals or other lycopene metabolites, whether produced by cleavage enzymes within the body or consumed with tomato products, can be found in tissues at concentrations equivalent to physiological retinoid concentrations. Therefore, it is plausible that lycopenoids, like retinoids, are bioactive within tissues. Androgen-independent DU145 prostate cancer cells were treated with lycopene, apo-8'-lycopenal, or apo-12'-lycopenal. DU145 cell proliferation was significantly reduced by supra-physiological levels of lycopene and apo-12'-lycopenal, in part, thro...

PC3 prostate tumor-initiating cells with molecular profile FAM65B(high)/MFI2(low)/LEF1(low) increase tumor angiogenesis

Molecular Cancer — Wed, 29 Dec 2010 00:00:00 +0100

Conclusions: These findings support the proposal that PC3 tumors are sustained by a small number of tumor-initiating cells with stem-like characteristics, including strong self-renewal and pro-angiogenic capability and marked by the expression pattern FAM65B(high)/MFI2(low)/LEF1(low). These markers may serve as targets for therapies designed to eliminate cancer stem cell populations associated with aggressive, androgen-independent prostate tumors such as PC3. (Source: Molecular Cancer)

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XAF1 expression and regulatory effects of somatostatin on XAF1 in prostate cancer cells

Journal of Experimental and Clinical Cancer Research — Sat, 11 Dec 2010 00:00:00 +0100

Conclusions: XAF1 down-regulation may contribute to the prostate cancer development. The enhanced XAF1 expression by somatostatin indicates a promising strategy for prostate cancer therapy. (Source: Journal of Experimental and Clinical Cancer Research)

Proteasomal Degradation of Sphingosine Kinase 1 [Lipids]

Journal of Biological Chemistry — Fri, 03 Dec 2010 00:00:00 +0100

Sphingosine kinase 1 (SK1) is an enzyme that catalyzes the phosphorylation of sphingosine to produce the bioactive lipid sphingosine 1-phosphate (S1P). We demonstrate here that the SK1 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole) induces the proteasomal degradation of SK1 in human pulmonary artery smooth muscle cells, androgen-sensitive LNCaP prostate cancer cells, MCF-7 and MCF-7 HER2 breast cancer cells and that this is likely mediated by ceramide as a consequence of catalytic inhibition of SK1 by SKi. Moreover, SK1 is polyubiquitinated under basal conditions, and SKi appears to increase the degradation of SK1 by activating the proteasome. In addition, the proteasomal degradation of SK1a and SK1b in androgen-sensitive LNCaP cells is associated with the induction of ap...

Intracellular adaptor molecules and AR signalling in the tumour microenvironment.

Cellular Signalling — Thu, 02 Dec 2010 00:00:00 +0100

Authors: Reebye V, Frilling A, Habib NA, Mintz PJ Androgen deprivation therapy is the mainstay for treating advanced prostate cancer. A better understanding in the complexity of the androgen receptor (AR) signalling pathway has highlighted that this form of treatment is not sufficient. Since Huggins and Hodges made their crucial observations on the benefits of castration for prostate cancer, significant progress has been achieved in understanding the importance of the cross-talk between the hormone signalling pathway and the kinase signalling network. We now know that preventing androgen production or ligand binding to the AR does not necessarily mark the end of the road for prostate tumour growth. Emerging evidence suggests that there exists a complex set of compensatory mechanisms wh...

Inhibition of Aberrant Androgen Receptor Induction of Prostate Specific Antigen Gene Expression, Cell Proliferation and Tumor Growth by 17α-Estradiol in Prostate Cancer

The Journal of Urology — Mon, 15 Nov 2010 00:00:00 +0100

Conclusions: Results suggest that 17α-estradiol with less classic estrogenic activity is a potential therapeutic agent for androgen independent prostate cancer due to androgen receptor mutation. (Source: The Journal of Urology)

Prostate cancer immunology – an update for Urologists

BJU International — Wed, 10 Nov 2010 00:00:00 +0100

A better understanding of the immune processes in the pathogenesis and progression of prostate cancer (CaP) may point the way towards improved treatment modalities. The challenge is to amplify immune responses to combat tumour escape mechanisms. Infection and inflammation may have a role in prostate carcinogenesis, including the newly discovered xenotropic murine leukaemia virus (XMRV). These inflammatory states damage defence mechanisms and induce a high proliferative state favouring further mutation and impaired immune surveillance. With this knowledge we are able to explore the use of immunotherapy to rejuvenate the immune system in combating CaP. Recently Sipuleucel‐T, an immunotherapeutic agent for metastatic androgen independent CaP, has resulted in improved survival and might be t...

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MnSOD drives neuroendocrine differentiation, androgen-independence and cell survival in prostate cancer cells.

Free Radical Biology and Medicine — Thu, 04 Nov 2010 00:00:00 +0100

Authors: Quiros-Gonzalez I, Sainz RM, Hevia D, Mayo JC An increase in neuroendocrine (NE) cells number has been associated with prostate tumor progression, one of the most frequent cancers among western males. We had previously reported that mitochondrial Manganese-Superoxide Dismutase (MnSOD) increases during the NE differentiation process. The goal was to find whether MnSOD up-regulation is enough to induce NE differentiation. Several human prostate cancer LNCaP cell clones stably overexpressing MnSOD were characterized and two were selected (MnSOD-S4 and MnSOD-S12). MnSOD overexpression induces NE morphological features as well as co-expression of the NE marker Synaptophysin. Both MnSOD clones exhibit lower superoxide levels and higher H(2)O(2) levels. MnSOD-overexpressing cells sho...

A phase II trial of weekly i.v. KW‐2170 in advanced castrate‐resistant prostate cancer

Asia-Pacific Journal of Clinical Oncology — Wed, 03 Nov 2010 00:00:00 +0100

Conclusion: KW‐2170 is a very well tolerated chemotherapy agent. It has a relatively low PSA response rate, and did not meet the pre‐specifed criteria for further studies. (Source: Asia-Pacific Journal of Clinical Oncology)

Suppression of human prostate cancer PC-3 cell growth by N-acetylcysteine involves overexpression of Cyr61.

Toxicology in Vitro — Tue, 02 Nov 2010 00:00:00 +0100

In this study, we investigated a growth-suppressive mechanism of NAC action in androgen-independent prostate carcinoma PC-3 cells. NAC (⩾1 mM) inhibited the proliferation of PC-3 cells in a dose- and time-dependent manner. Moreover, NAC treatment suppressed the activation of NF-κB induced by IKK- as detected by the NF-κB reporter gene assay. NAC exerted a biphasic effect on the intracellular ROS levels depending on incubation time; the antioxidant effect was seen within 2 h after NAC treatment, however, a pro-oxidant effect was evident after 48 h treatment. In addition to these effects, NAC treatment elicited a dose- and time-dependent increase in the Cyr61 expression that was accompanied by an increase in its mRNA and blocked by cycloheximide pretreatment. Importantly, NAC treatment c...

Secretory phospholipase A2-IIa is involved in prostate cancer progression and may potentially serve as a biomarker for prostate cancer

Carcinogenesis — Fri, 29 Oct 2010 00:00:00 +0100

The majority of prostate cancers are indolent, whereas a significant portion of patients will require systemic treatment during the course of their disease. To date, only high Gleason scores are best associated with a poor prognosis in prostate cancer. No validated serum biomarker has been identified with prognostic power. Previous studies showed that secretory phospholipase A2-IIa (sPLA2-IIa) is overexpressed in almost all human prostate cancer specimens and its elevated levels are correlated with high tumor grade. Here, we found that sPLA2-IIa is overexpressed in androgen-independent prostate cancer LNCaP-AI cells relative to their androgen-dependent LNCaP cell counterparts. LNCaP-AI cells also secrete significantly higher levels of sPLA2-IIa. Blocking sPLA2-IIa function compromises andr...

Pregnane X Receptor As a Therapeutic Target to Inhibit Androgen Activity.

Endocrinology — Tue, 19 Oct 2010 23:00:00 +0100

Authors: Zhang B, Cheng Q, Ou Z, Lee JH, Xu M, Kochhar U, Ren S, Huang M, Pflug BR, Xie W The androgen-androgen receptor signaling pathway plays an important role in the pathogenesis of prostate cancer. Accordingly, androgen deprivation has been the most effective endocrine therapy for hormone-dependent prostate cancer. Here, we report a novel pregnane X receptor (PXR)-mediated and metabolism-based mechanism to reduce androgenic tone. PXR is a nuclear receptor previously known as a xenobiotic receptor regulating the expression of drug metabolizing enzymes and transporters. We showed that genetic (using a PXR transgene) or pharmacological (using a PXR agonist) activation of PXR lowered androgenic activity and inhibited androgen-dependent prostate regeneration in castrated male mice that...

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Aurora-A Phosphorylates AR [Molecular Bases Of Disease]

Journal of Biological Chemistry — Thu, 14 Oct 2010 23:00:00 +0100

In this study, we demonstrate elevated levels of Aurora-A in androgen-refractory LNCaP-RF but not androgen-sensitive LNCaP cells, which prompted us to examine whether Aurora-A regulates the androgen receptor (AR) and whether elevated Aurora-A is involved in androgen-independent cell growth. We show that ectopic expression of Aurora-A induces AR transactivation activity in the presence and absence of androgen. Aurora-A interacts with AR and phosphorylates AR at Thr282 and Ser293 in vitro and in vivo. Aurora-A induces AR transactivation activity in a phosphorylation-dependent manner. Ectopic expression of Aurora-A in LNCaP cells induces prostate-specific antigen expression and cell survival, whereas knockdown of Aurora-A sensitizes LNCaP-RF cells to apoptosis and cell growth arrest. These da...

Thioredoxin 1 as a subcellular biomarker of redox imbalance in human prostate cancer progression.

Free Radical Biology and Medicine — Thu, 14 Oct 2010 23:00:00 +0100

Authors: Shan W, Zhong W, Zhao R, Oberley TD We determined protein levels and subcellular distribution of thioredoxin 1 (Trx1) in human prostate tissues using tissue microarrays and analyzed redox changes of Trx1 in the nucleus and cytoplasm in cell culture models with redox western blot technique. We demonstrated increased nuclear Trx1 levels in high- versus low-grade human prostate cancers. Despite increased protein levels, the oxidized forms of nuclear Trx1 were higher in prostate cancer cell lines compared to their benign counterparts, suggesting that nuclear redox imbalance occurred selectively in cancer cells. A growth-stimulating dose of androgen caused transient oxidation of Trx1 in androgen-responsive prostate cancer cells only, suggesting a loss of both androgen- and redox-si...

RasGRP3 Contributes to Formation and Maintenance of the Prostate Cancer Phenotype

Cancer Research — Tue, 12 Oct 2010 23:00:00 +0100

RasGRP3 mediates the activation of the Ras signaling pathway that is present in many human cancers. Here, we explored the involvement of RasGRP3 in the formation and maintenance of the prostate cancer phenotype. RasGRP3 expression was elevated in multiple human prostate tumor tissue samples and in the human androgen-independent prostate cancer cell lines PC-3 and DU 145 compared with the androgen-dependent prostate cancer cell line LNCaP. Downregulation of endogenous RasGRP3 in PC-3 and DU 145 cells reduced Ras-GTP formation, inhibited cell proliferation, impeded cell migration, and induced apoptosis. Anchorage-independent growth of the PC-3 cells and tumor formation in mouse xenografts of both cell lines were likewise inhibited. Inhibition of RasGRP3 expression reduced AKT and extracellul...

The PPARγ ligand ciglitazone regulates androgen receptor activation differently in androgen- dependent versus androgen- independent human prostate cancer cells.

Experimental Cell Research — Sun, 03 Oct 2010 23:00:00 +0100

Authors: Moss PE, Lyles BE, Stewart LV The androgen receptor (AR) regulates growth and progression of androgen-dependent as well as androgen-independent prostate cancer cells. Peroxisome proliferator activated receptor gamma (PPARγ) agonists have been reported to reduce AR activation in androgen-dependent LNCaP prostate cancer cells. To determine whether PPARγ ligands are equally effective at inhibiting AR activity in androgen-independent prostate cancer, we examined the effect of the PPARγ ligands ciglitazone and rosiglitazone on C4-2 cells, an androgen- independent derivative of the LNCaP cell line. Luciferase-based reporter assays and Western blot analysis demonstrated PPARγ ligand reduced dihydrotestosterone (DHT)-induced increases in AR activity in LNCaP cells. However, in C4-...

[Comment] Cabazitaxel in prostate cancer: stretching a string

LANCET — Thu, 30 Sep 2010 23:00:00 +0100

Improvements in the survival of patients who are at the fatal edge of the prostate-cancer kaleidoscope have been difficult to come by. Trial accrual and practice-changing results for hormone-refractory, castration-resistant, or androgen-independent prostate cancer, each a fatal malady, have lagged 20 years behind those for breast cancer. In 1996, the National Cancer Institute of Canada investigators reported that, compared to prednisone alone, mitoxantrone with prednisone improved quality of life and symptoms for a median of 6 months, but had a negligible effect on survival. These data were summarised in a subsequent Cancer and Leukemia Group B (CALGB) trial. In 2004, the Southwest Oncology Group (SWOG)-S9916 trial of docetaxel-based chemotherapy compared to mitoxantrone, and the TAX 327 t...

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Early response assessment in prostate carcinoma by 18F-fluorothymidine following anticancer therapy with docetaxel using preclinical tumour models

European Journal of Nuclear Medicine and Molecular Imaging — Wed, 29 Sep 2010 05:43:55 +0100

Conclusion These results indicate that FLT is a promising tracer for monitoring the early effects of anticancer therapy with DTX in patients with HRPC. Content Type Journal ArticleDOI 10.1007/s00259-010-1613-zAuthors Nobuyuki Oyama, Department of Urology, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka-Shimoaizuki, Fukui, 9101193 JapanYoko Hasegawa, Department of Urology, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka-Shimoaizuki, Fukui, 9101193 JapanYasushi Kiyono, Biomedical Imaging Research Center, University of Fukui, Fukui, JapanMasato Kobayashi, Biomedical Imaging Research Center, University of Fukui, Fukui, JapanYasuhisa Fujibayashi, Biomedical Imaging Research Center, University of Fukui, Fukui, JapanDatta E. Ponde, Mallinckro...

RNA interference targeting mutant p53 inhibits growth and induces apoptosis in DU145 human prostate cancer cells

Medical Oncology — Tue, 21 Sep 2010 11:27:29 +0100

Abstract p53 is the most frequently mutated tumor suppressor gene in human cancer. Recent studies have indicated that p53 mutants not only lose tumor suppression activity but also gain novel oncogenic functions that contribute to tumor malignancy. In this study, we explored mutant p53 as a target for novel anti-cancer treatment in prostate cancer. Using the DU145 human androgen-independent prostate cancer cell line, we show that silencing of mutant p53 gene by RNA interference led to significant inhibition of cell viability and growth, which was associated with cell cycle arrest at G1 and G2/M phase, and ultimately induced massive apoptosis. Mechanistically, p53-siRNA inhibited phosphatidylinositol 3′-kinase/Akt signaling pathway, which might be responsible for the reduc...

Paxillin Regulation of Nongenomic Androgen Actions [Signal Transduction]

Journal of Biological Chemistry — Fri, 03 Sep 2010 13:38:15 +0100

Although transcriptional effects of androgens have been extensively studied, mechanisms regulating transcription-independent (nongenomic) androgen actions are poorly understood. Previously, we have shown that paxillin, a multidomain adaptor protein, is a critical regulator of testosterone-induced MAPK-signaling during Xenopus oocyte maturation. Here we examine the nongenomic effects of dihydrotestosterone (DHT) in prostate cancer cells, focusing on how paxillin mediates Erk signaling and downstream physiologic actions. We show that in LnCAP cells DHT functions as a growth factor that indirectly activates the EGF-receptor (EGFR) via androgen receptor binding and matrix metalloproteinase-mediated release of EGFR ligands. Interestingly, siRNA-mediated knockdown of paxillin expression in andro...

E3 Ubiquitin Protein Ligase, E6-Associated Protein (E6-AP) Regulates PI3K-Akt Signaling and Prostate Cell Growth.

Biochimica et Biophysica Acta — Thu, 02 Sep 2010 23:00:00 +0100

This study elucidates the role of E6-associated protein, E6-AP (a dual function steroid hormone receptor coactivator and ubiquitin-protein ligase) in the regulation of PI3K-Akt signaling pathway, prostate gland growth and proliferation. Here, we report the generation of transgenic mice and prostate cancer cell line, LNCaP cells that overexpress E6-AP protein. Using these models we show that the levels of total Akt and phosphorylated Akt (active Akt) are increased in E6-AP overexpressing prostate gland and LNCaP cells suggesting that E6-AP regulates the PI3K-Akt signaling pathway. The prostate glands in our transgenic mice are ~20% larger and produce preneoplastic lesions at the age of 18months. Our data also suggest that E6-AP modulates PI3K-Akt signaling pathway by both androgen-independe...

FBI-1 functions as a novel AR co-repressor in prostate cancer cells.

Cellular and Molecular Life Sciences : CMLS — Wed, 01 Sep 2010 23:00:00 +0100

In this study, we investigated a potential interaction between androgen receptor (AR) signaling and FBI-1 and demonstrated that overexpression of FBI-1 inhibited ligand-dependent AR activation. A protein-protein interaction was identified between FBI-1 and AR in a ligand-dependent manner. Furthermore, FBI-1, AR and SMRT formed a ternary complex and FBI-1 enhanced the recruitment of NCoR and SMRT to endogenous PSA upstream sequences. Our data also indicated that the FBI-1-mediated inhibition of AR transcriptional activity is partially dependent on HDAC. Interestingly, FBI-1 plays distinct roles in regulating LNCaP (androgen-dependent) and PC-3 cell (androgen-independent) proliferation. PMID: 20812024 [PubMed - as supplied by publisher] (Source: Cellular and Molecular Life Sciences : CML...

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Local prolactin is a target to prevent expansion of basal/stem cells in prostate tumors [Medical_Sciences]

Proceedings of the National Academy of Sciences — Tue, 24 Aug 2010 16:48:01 +0100

Androgen-independent recurrence is the major limit of androgen ablation therapy for prostate cancer. Identification of alternative pathways promoting prostate tumor... (Source: Proceedings of the National Academy of Sciences)

Recovery of hormone sensitivity after salvage brachytherapy for hormone refractory localized prostate cancer

International Braz J Urol — Sun, 22 Aug 2010 08:06:55 +0100

CONCLUSIONS: Hormone sensitivity may be recovered after salvage brachytherapy. Potential mechanisms underlying these observations are discussed and the likely central role of the activity of the androgen receptor highlighted. The relevance of these findings to the management of advanced prostate cancer is considered including thoughts on the practice of intermittent anti-androgen therapy. (Source: International Braz J Urol)

Androgen receptor signaling and mutations in prostate cancer.

Asian Journal of Andrology — Sun, 15 Aug 2010 23:00:00 +0100

Authors: Koochekpour S Normal and neoplastic growth of the prostate gland are dependent on androgen receptor (AR) expression and function. Androgenic activation of the AR, in association with its coregulatory factors, is the classical pathway that leads to transcriptional activity of AR target genes. Alternatively, cytoplasmic signaling crosstalk of AR by growth factors, neurotrophic peptides, cytokines or nonandrogenic hormones may have important roles in prostate carcinogenesis and in metastatic or androgen-independent (AI) progression of the disease. In addition, cross-modulation by various nuclear transcription factors acting through basal transcriptional machinery could positively or negatively affect the AR or AR target genes expression and activity. Androgen ablation leads to an...

Survivin gene silencing sensitizes prostate cancer cells to selenium growth inhibition

BMC Cancer — Mon, 09 Aug 2010 23:00:00 +0100

Conclusions: Selenium could inhibit the growth of hormone-refractory prostate cancer cells both in vitro and in vivo, but the effects were modest. The growth inhibition was not mediated by downregulating survivin expression. Survivin silencing greatly enhanced the growth inhibitory effects of selenium. (Source: BMC Cancer)

A novel anticancer agent, retigeric acid B, displays proliferation inhibition, S phase arrest and apoptosis activation in human prostate cancer cells.

Chemico-Biological Interactions — Thu, 05 Aug 2010 23:00:00 +0100

Authors: Liu H, Liu YQ, Liu YQ, Xu AH, Young CY, Yuan HQ, Lou HX Retigeric acid B (RB), a naturally occurring pentacyclic triterpenic acid, has been noted for its antifungal properties in vitro. Here, we observed that RB inhibited prostate cancer cell proliferation and induced cell death in a dose-dependent manner, but exerted very little inhibitory effect on noncancerous prostate epithelial cell viability. Treatment of androgen-independent PC-3 cells with RB caused a moderate increase in p21(Cip1), and enforced the cell cycle arrest in the S phase. A block of S phase was accompanied with decreases in cyclin B, and increases in cyclin E and cyclin A proteins and phosphorylated retinoblastoma protein (pRb), whereas the expression of cdk2 remained almost unchanged in PC-3 cells exposed t...

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Fisetin induces autophagic cell death through suppression of mTOR signaling pathway in prostate cancer cells

Carcinogenesis — Wed, 04 Aug 2010 12:50:39 +0100

The mammalian target of rapamycin (mTOR) kinase is an important component of PTEN/PI3K/Akt signaling pathway, which is frequently deregulated in prostate cancer (CaP). Recent studies suggest that targeting PTEN/PI3K/Akt and mTOR signaling pathway could be an effective strategy for the treatment of hormone refractory CaP. Here, we show that the treatment of androgen-independent and PTEN-negative human CaP PC3 cells with fisetin, a dietary flavonoid, resulted in inhibition of mTOR kinase signaling pathway. Treatment of cells with fisetin inhibited mTOR activity and downregulated Raptor, Rictor, PRAS40 and GβL that resulted in loss of mTOR complexes (mTORC)1/2 formation. Fisetin also activated the mTOR repressor TSC2 through inhibition of Akt and activation of AMPK. Fisetin-mediated inhi...

ECE-1 influences prostate cancer cell invasion via ET-1-mediated FAK phosphorylation and ET-1-independent mechanisms.

Canadian Journal of Physiology and Pharmacology — Sat, 31 Jul 2010 23:00:00 +0100

In conclusion, ECE-1 influences PC cell invasion via both ET-1-mediated FAK phosphorylation and ET-1 independent mechanisms. PMID: 20725143 [PubMed - in process] (Source: Canadian Journal of Physiology and Pharmacology)

Prostate cancer chemopreventive activity of phenethyl isothiocyanate through epigenetic regulation (Review).

International Journal of Oncology — Sat, 31 Jul 2010 21:06:51 +0100

Authors: Wang LG, Chiao JW Prostate cancer is one of the most commonly diagnosed cancers in men. The number of affected men is expected to rapidly increase as the population of males over the age of 50 grows worldwide. For patients who are not cured by local treatment and experience metastatic disease, neither androgen ablation nor chemotherapy can abrogate progression and death from androgen-independent/hormone-refractory disease. Therefore, finding strategies for the prevention of prostate cancer initiation and disease progression is a medical challenge. Consumption of cruciferous vegetables has been reported to be associated with reduced incidence of prostate cancer cases. The isothiocyanates, including phenethyl isothiocyanate (PEITC), from cruciferous vegetables have been demonstr...

Quercetin regulates insulin like growth factor signaling and induces intrinsic and extrinsic pathway mediated apoptosis in androgen independent prostate cancer cells (PC-3).

Molecular and Cellular Biochemistry — Sat, 24 Jul 2010 23:00:00 +0100

This study suggests that quercetin decreases the survival of androgen independent prostate cancer cells by modulating the expression of insulin-like growth factors (IGF) system components, signaling molecules and induces apoptosis, which could be very useful for the androgen independent prostate cancer treatment. PMID: 20658310 [PubMed - as supplied by publisher] (Source: Molecular and Cellular Biochemistry)

Human Prostatic Acid Phosphatase, an Authentic Tyrosine Phosphatase, Dephosphorylates ErbB-2 and Regulates Prostate Cancer Cell Growth [Signal Transduction]

Journal of Biological Chemistry — Fri, 23 Jul 2010 13:37:12 +0100

In this report, our data show that the phosphorylation level of ErbB-2 primarily at Tyr1221/2 correlates with the growth rate of both LNCaP and MDA PCa2b human PCa cells. Further, cPAcP reciprocally co-immunoprecipitated with ErbB-2 in a non-permissive growth condition. Expression of wild type cPAcP, but not inactive mutant, by cDNA in cPAcP-null LNCaP C-81 cells results in decreased tyrosine phosphorylation of ErbB-2 including Tyr1221/2. Concurrently, Tyr317 phosphorylation of p52Shc, proliferating cell nuclear antigen expression, and cell growth are decreased in these cells. Conversely, decreased cPAcP expression by short hairpin RNA in LNCaP C-33 cells was associated with elevated phosphorylation of ErbB-2 initially at Tyr1221/2. Its downstream p52Shc, ERK1/2, Akt, Src, STAT-3, and STAT...

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HIF1alfa isoforms in benign and malignant prostate tissue and their correlation to neuroendocrine differentiation

BMC Cancer — Tue, 20 Jul 2010 23:00:00 +0100

Conclusion: Our results indicate that the cytoplasmic stablization of HIF1alfa in NE-differentiated cells in benign and malignant prostate tissue is due to presence of an HIF1alfa isoform, HIF1alfa1.2. Co-localization of this isoform with HIF1beta indicated that the HIF1alfa1.2 isoform might sequester HIF1beta in the cytoplasm. (Source: BMC Cancer)

New Target For Treatment Of Advanced Prostate Cancer

Health News from Medical News Today — Wed, 07 Jul 2010 09:00:00 +0100

In its early stages, prostate cancer requires androgens (hormones that promote the development and maintenance of male sex characteristics) for growth, and current first-line therapies target the receptor for these hormones to slow cancer's development and spread. However, advanced prostate cancers are often androgen-independent, meaning that androgen-blocking therapies are ineffective. Scientists aren't sure how this shift occurs as prostate cancer advances. One idea is that prostate cancer cells acquire the ability to make their own androgen... (Source: Health News from Medical News Today)

MAPKs Are Not Involved in Triptolide-Induced Cell Growth Inhibition and Apoptosis in Prostate Cancer Cell Lines with Different p53 Status

Planta Medica — Wed, 07 Jul 2010 05:31:56 +0100

Planta MedDOI: 10.1055/s-0030-1250076AbstractTriptolide showed excellent antitumor activity against several solid tumors. However, its mechanism has not been fully understood. To further elucidate it, the effects of mitogen activated protein kinases (MAPKs) on the activity of triptolide towards prostate cancer cell lines were investigated in the present study using both LNCaP (p53 positive and androgen-dependent) and PC-3 (p53 deficient and androgen-independent) cells. Our results showed that triptolide exerted potent growth inhibitory and apoptotic effects on both cell lines, and the effects were independent of the expression of p53. Although upregulation of ERK and JNK phosphorylation was observed after the triptolide treatment, the results with inhibitors showed that these MAPKs were no...

Anti-proliferative effect of a triazole derivative (ST1959) on LNCaP human prostate cancer cells through down-regulation of cyclin and androgen receptor expression

The Prostate — Mon, 05 Jul 2010 23:00:00 +0100

In this study, we sought to ascertain the effects of ST1959 on the growth of androgen-dependent and androgen-independent prostate cancer (PCa) cells.The growth of androgen-dependent (LNCaP) and androgen-independent (PC3, DU-145) cells was analyzed in vitro both in the presence and absence of ST1959. Modulation of cyclin and androgen receptor (AR) expression following treatment with ST1959 was analyzed by Western blot and cytofluorimetric analysis.We observed that ST1959 causes a significant growth inhibition of LNCaP cells without affecting proliferation of androgen-insensitive DU-145 and PC3 cell lines. These effects were associated with G0/G1 cell cycle arrest and down-regulation of cyclin D1, A and B and AR expression.Our present findings indicate that the anti-proliferative activity of...

1,4-Phenylenebis(Methylene)Selenocyanate, but Not Selenomethionine, Inhibits Androgen Receptor and Akt Signaling in Human Prostate Cancer Cells.

Cell Research — Mon, 05 Jul 2010 23:00:00 +0100

Authors: Facompre ND, El-Bayoumy K, Sun YW, Pinto JT, Sinha R The lack of treatment for worried-well patients with high-grade prostatic intraepithelial neoplasia combined with issues of recurrence and hormone resistance in prostate cancer survivors remains a major public health obstacle. The long latency of prostate cancer development provides an opportunity to intervene with agents of known mechanisms at various stages of disease progression. A number of signaling cascades have been shown to play important roles in prostate cancer development and progression, including the androgen receptor (AR) and phosphatidylinositol 3-kinase/Akt signaling pathways. Crosstalk between these two pathways is also thought to contribute to progression and hormone-refractory prostate disease. Our initial...

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MAPKs Are Not Involved in Triptolide-Induced Cell Growth Inhibition and Apoptosis in Prostate Cancer Cell Lines with Different p53 Status

Planta Medica — Mon, 05 Jul 2010 23:00:00 +0100

Commentary on Telomerase enzyme inhibition (TEI) and cytolytic therapy in the management of androgen independent osseous metastatic prostate cancer Li Y, Malaeb BS, Li ZZ, Thompson MG, Chen Z, Corey DR, Hsieh JT, Shay JW, Koeneman KS, Department of Urologic Surgery, Center for Prostate Cancer, University of Minnesota, Minneapolis, MN.

Urologic Oncology — Wed, 30 Jun 2010 23:00:00 +0100

Authors: Koeneman KS PMID: 20610286 [PubMed - in process] (Source: Urologic Oncology)

Commentary on Telomerase enzyme inhibition (TEI) and cytolytic therapy in the management of androgen independent osseous metastatic prostate cancer: Li Y, Malaeb BS, Li ZZ, Thompson MG, Chen Z, Corey DR, Hsieh JT, Shay JW, Koeneman KS, Department of Urologic Surgery, Center for Prostate Cancer, University of Minnesota, Minneapolis, MN

Urologic Oncology: Seminars and Original Investigations — Tue, 29 Jun 2010 07:07:51 +0100

Prostate 2009 Dec 30 [Epub ahead of print] 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. (Source: Urologic Oncology: Seminars and Original Investigations)

Involvement of microRNA-21 in mediating chemo-resistance to docetaxel in androgen-independent prostate cancer PC3 cells.

Acta Pharmacologica Sinica — Sun, 27 Jun 2010 23:00:00 +0100

Conclusion:Our findings suggest that miR-21 contributed to the resistance of PC3 cells to docetaxel, and that targeting miR-21 may offer a promising therapeutic approach in sensitizing prostate cancer to docetaxel treatment. PMID: 20581857 [PubMed - as supplied by publisher] (Source: Acta Pharmacologica Sinica)

The ubiquitin-proteasome system in prostate cancer and its transition to castration resistance.

Urologic Oncology — Wed, 23 Jun 2010 23:00:00 +0100

Authors: Voutsadakis IA, Papandreou CN Prostate cancer is the most common carcinoma in the male population. In its initial stage, the disease is androgen-dependent and responds therapeutically to androgen deprivation treatment but it usually progresses after a few years to an androgen-independent phase that is refractory to hormonal manipulations. The proteasome is a multi-unit protease system that regulates the abundance and function of a significant number of cell proteins, and its inhibition results in cancer cell growth inhibition and apoptosis and is already exploited in the clinic with the use of proteasome inhibitor bortezomib in multiple myeloma. In order to be recognized by the proteasome, a target protein needs to be linked to a chain of the small protein ubiquitin. In this p...

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Changes in caveolae, caveolin, and polymerase 1 and transcript release factor (PTRF) expression in prostate cancer progression

The Prostate — Tue, 15 Jun 2010 23:00:00 +0100

This study demonstrates that changes in the cell membrane involving loss of caveolae and PTRF expression occur with the development of prostate cancer. These changes are accompanied by an up-regulation of caveolin-2. Prostate © 2010 Wiley-Liss, Inc. (Source: The Prostate)

ADAMTS1 alters blood vessel morphology and TSP1 levels in LNCaP and LNCaP-19 prostate tumors

BMC Cancer — Sun, 13 Jun 2010 23:00:00 +0100

Conclusions: The present study demonstrates that ADAMTS1 is an important regulatory factor of angiogenesis and tumor growth in prostate tumors, where modified ADAMTS1 expression resulted in markedly changed blood vessel morphology, possibly related to altered TSP1 levels. (Source: BMC Cancer)

Sorafenib induces apoptosis and autophagy in prostate cancer cells in vitro.

International Journal of Oncology — Fri, 04 Jun 2010 19:58:12 +0100

Authors: UllÃ©n A, Farnebo M, Thyrell L, Mahmoudi S, Kharaziha P, Lennartsson L, GrandÃ©r D, Panaretakis T, Nilsson S The multiple tyrosine kinase inhibitor sorafenib has recently demonstrated clinical effects in patients with androgen-independent prostate cancer. These observations provided the rational for investigating the anti-tumoral properties of this compound on prostate cancer cell lines at the molecular level. Two hormone refractory (PC3 and DU145) and one hormone responsive cell line (22Rv1) were used. By use of a panel of cell biology techniques such as immunoblotting, flow cytometry and immunocytochemistry, effects on the MAPK pathway and induction of apoptosis and autophagy were evaluated. We demonstrate that sorafenib reduced cell viability in a dose-dependent manner,...

Expression and function of ATIP/MTUS1 in human prostate cancer cell lines

The Prostate — Tue, 01 Jun 2010 23:00:00 +0100

We have previously demonstrated Ang II type 2 (AT2-) receptor-mediated inhibition of EGF-induced prostate cancer cell growth in androgen-dependent (LNCaP) and independent (PC3) prostate cancer cell lines.To explore the signaling pathways involved in this inhibitory effect, we examined the interaction of the AT2-receptor with its novel regulatory partner ATIP using real time PCR, over-expression, siRNA and [3H]thymidine incorporation assays.The results in human prostate cancer cell lines demonstrate the presence of ATIP in both cell lines examined, and suggest that (i) the AT2-receptor through an interaction with ATIP mediates an anti-growth factor effect in both androgen-dependent and androgen-independent cell lines; (ii) ATIP expression decreases as the rate of cell growth and androgen-in...

Pim1 promotes human prostate cancer cell tumorigenicity and c-MYC transcriptional activity

BMC Cancer — Mon, 31 May 2010 23:00:00 +0100

Conclusion: Our results suggest an in vivo role of Pim1 in promoting prostate tumorigenesis although it displayed distinct oncogenic activities depending on the disease stage of the cell line. Pim1 promotes tumorigenicity at least in part by enhancing c-MYC transcriptional activity. We also made the novel discovery that treatment of cells with the c-MYC inhibitor 10058-F4 leads to a reduction in Pim1 protein levels. (Source: BMC Cancer)

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[11C]Choline as pharmacodynamic marker for therapy response assessment in a prostate cancer xenograft model

European Journal of Nuclear Medicine and Molecular Imaging — Sat, 29 May 2010 16:53:32 +0100

Conclusion Our results demonstrate that [11C]choline has the potential for use in the early monitoring of the therapeutic effect of docetaxel in a prostate cancer xenograft animal model. The results also indicate that PET with radioactively labelled choline derivatives might be a useful tool for monitoring responses to taxane-based chemotherapy in patients with advanced prostate cancer. Content Type Journal ArticleCategory Original ArticleDOI 10.1007/s00259-010-1493-2Authors Bernd J. Krause, Technische Universität München Department of Nuclear Medicine, Klinikum rechts der Isar Ismaninger Str. 22 81675 München, Munich GermanyMichael Souvatzoglou, Technische Universität München Department of Nuclear Medicine, Klinikum rechts der Isar Ismaninger Str. 22 81675 Mü...

HOXB13 promotes androgen independent growth of LNCaP prostate cancer cells by the activation of E2F signaling

Molecular Cancer — Wed, 26 May 2010 23:00:00 +0100

Conclusions: Taken together, the results of this study demonstrated the presence of a novel pathway that helps understand androgen-independent survival of prostate cancer cells. These findings suggest that upregulation of HOXB13 is associated with an additive growth advantage of prostate cancer cells in the absence of or low androgen concentrations, by the regulation of p21-mediated E2F signaling. (Source: Molecular Cancer)

Columbia University Study Shows Modified Citrus Pectin Fights Prostate Cancer

Health News from Medical News Today — Sat, 22 May 2010 08:00:00 +0100

Researchers at Columbia University recently analyzed the positive effects of Modified Citrus Pectin (MCP) on human and mouse prostate cancer cell lines. The results, as reported by lead researcher Dr. Aaron Katz in the online-first publication of Integrative Cancer Therapies, show that MCP inhibits cell proliferation and induces apoptosis (programmed cell death) in both androgen-dependent and androgen-independent cancer cells in a time and dose-dependent manner. Prostate cancer is the second leading cause of cancer death in men, and 1 in 6 will get prostate cancer during his lifetime. Dr... (Source: Health News from Medical News Today)

Adjuvants for cancer vaccines.

Seminars in Immunology — Mon, 17 May 2010 23:00:00 +0100

Authors: Dubensky TW, Reed SG The recent FDA approval of sipuleucel-T (Provenge((R))), a patient-specific immunotherapy for androgen-independent prostate cancer developed by Dendreon Corporation, has provided support for the concept of cellular immunotherapy as an approach to cancer treatment. Adjuvants are compounds that enhance the potency of the antigen-specific immune response and can be an essential component of an efficacious vaccine. Cervarix is a prophylactic vaccine against human papilloma virus (HPV) types 16 and 18, which can cause cervical cancer, and recently received approval from the FDA, due in part to the protective immunity it conferred against not only HPV types contained in the vaccine but in addition to oncogenic HPV strains that were not contained in the vaccine. ...

MicroRNA-101 negatively regulates Ezh2 and its expression is modulated by androgen receptor and HIF-1alpha/HIF-1beta

Molecular Cancer — Sun, 16 May 2010 23:00:00 +0100

Conclusions: This study indicates that miR-101 targets Ezh2 and decreases the invasiveness of PCa cells, suggesting that miR-101 introduction is a potential therapeutic strategy to combat PCa. MiR-101 differentially regulates prostate cell proliferation. Meanwhile, the expression of miR-101 is also modulated at different physiological conditions, such as androgen stimulation and HIF-1alpha/HIF-1beta induction. (Source: Molecular Cancer)

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The multikinase inhibitor sorafenib induces caspase-dependent apoptosis in PC-3 prostate cancer cells.

Asian Journal of Andrology — Sun, 16 May 2010 23:00:00 +0100

In conclusion, sorafenib induces apoptosis through a caspase-dependent mechanism with down-regulated anti-apoptotic proteins in androgen-independent prostate cancer cells in vitro. PMID: 20473320 [PubMed - as supplied by publisher] (Source: Asian Journal of Andrology)

Differential CARM1 expression in prostate and colorectal cancers

BMC Cancer — Wed, 12 May 2010 23:00:00 +0100

Conclusions: The results of this study suggest that, in addition to its role in activation of steroid receptors, CARM1 functions as a transcriptional modulator by altering the activity of many transcriptional factors, especially with regard to androgen independent PCa and colorectal cancers. (Source: BMC Cancer)

Osteoblasts can stimulate prostate cancer growth and transcriptionally down-regulate PSA expression in cell line models

Urologic Oncology: Seminars and Original Investigations — Mon, 10 May 2010 04:00:00 +0100

Conclusions: The osteoblastic environment stimulates prostate cancer cell proliferation but reduces PSA production initially. The mechanism of PSA down-regulation is transcriptional, most likely in response to soluble factors present in the osteoblastic bone stromal cell CM. Transcriptional down-regulation appears to be mediated by elements near both the TATA box and the AREIII component. (Source: Urologic Oncology: Seminars and Original Investigations)

Osteoblasts can stimulate prostate cancer growth and transcriptionally down-regulate PSA expression in cell line models.

Urologic Oncology — Tue, 04 May 2010 23:00:00 +0100

CONCLUSIONS: The osteoblastic environment stimulates prostate cancer cell proliferation but reduces PSA production initially. The mechanism of PSA down-regulation is transcriptional, most likely in response to soluble factors present in the osteoblastic bone stromal cell CM. Transcriptional down-regulation appears to be mediated by elements near both the TATA box and the ARE(III) component. PMID: 20451417 [PubMed - as supplied by publisher] (Source: Urologic Oncology)

Hedgehog/Gli supports androgen signaling in androgen deprived and androgen independent prostate cancer cells

Molecular Cancer — Sun, 25 Apr 2010 23:00:00 +0100

Conclusions: Collectively, our results indicate that Hh/Gli signaling supports androgen signaling and AI growth in prostate cancer cells in a low androgen environment. The finding that Gli2 co-immunoprecipitates with AR protein suggests that an interaction between these proteins might be the basis for Hedgehog/Gli support of androgen signaling under this condition. (Source: Molecular Cancer)

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Evaluation of Cisplatin in Combination with β-Elemene as a Regimen for Prostate Cancer Chemotherapy

Basic and Clinical Pharmacology and Toxicology — Fri, 23 Apr 2010 23:00:00 +0100

Abstract: Cisplatin is one of the most potent chemotherapeutic agents for the treatment of many types of solid tumours. Nevertheless, it is not the first-line drug for prostate cancer chemotherapy, because prostate tumour cells exhibit intrinsic and acquired resistance to cisplatin. We have previously demonstrated that [beta]-elemene, a novel plant-derived anti-neoplastic with low toxicity, inhibits lung and ovarian carcinoma cell growth in vitro. In the present study, we explored the therapeutically chemosensitizing effect of [beta]-elemene on cisplatin anti-tumour efficacy in androgen-independent prostate cancer cells as well as the underlying mechanism. [beta]-Elemene significantly increased cisplatin cytotoxicity in the androgen-independent prostate carcinoma cell lines DU145 and PC-3....

Cryptocaryone, a Natural Dihydrochalcone, Induces Apoptosis in Human Androgen Independent Prostate Cancer Cells by Death Receptor Clustering in Lipid Raft and Nonraft Compartments

The Journal of Urology — Sun, 18 Apr 2010 23:00:00 +0100

Conclusions: We suggest that cryptocaryone has anticancer activity via the stimulation of death receptor and associated molecule clustering, leading to caspase-8 and 3 activation, and apoptosis in prostate cancer cells. (Source: The Journal of Urology)

Shepherding AKT and androgen receptor by Ack1 tyrosine kinase

Journal of Cellular Physiology — Fri, 16 Apr 2010 23:00:00 +0100

Ack1 (also known as ACK, TNK2, or activated Cdc42 kinase) is a structurally unique non-receptor tyrosine kinase that is expressed in diverse cell types. It integrates signals from plethora of ligand-activated receptor tyrosine kinases (RTKs), for example, MERTK, EGFR, HER2, PDGFR and insulin receptor to initiate intracellular signaling cascades. Ack1 transduces extracellular signals to cytosolic and nuclear effectors such as the protein kinase AKT/PKB and androgen receptor (AR), to promote cell survival and growth. While tyrosine phosphorylation of AR at Tyr267 regulates androgen-independent recruitment of AR to the androgen-responsive enhancers and transcription of AR target genes to drive prostate cancer progression, phosphorylation of an evolutionarily conserved Tyrosine 176 in the kina...

KLK5 gene expression is severely upregulated in androgen-independent prostate cancer cells after treatment with the chemotherapeutic agents docetaxel and mitoxantrone

Biological Chemistry — Fri, 16 Apr 2010 15:21:29 +0100

Biological Chemistry 391 (4): 467-474 Abstract Kallikrein-related peptidases (KLKs), including KLK5, have been proposed as promising biomarkers for prostate cancer diagnosis and prognosis. In the present study, we report that distinct augmentations (up to 6.4-fold) of KLK5 mRNA expressional levels, calculated via quantitative real-time PCR, occur after treatment of DU145 cells with appropriate concentrations, determined by the MTT method, of docetaxel and mitoxantrone. Our data reveal the endogenous need of prostate cancer cells for modified KLK5 expression to cope with the administration of chemotherapeutic drugs. Furthermore, it is proposed that the expression profile of KLK5 could serve as a putative biomarker for monitoring the treatment response in hormone refractory prostate cancer p...

Aberrant Activation of the Androgen Receptor by NF-{kappa}B2/p52 in Prostate Cancer Cells

Cancer Research — Thu, 15 Apr 2010 04:08:45 +0100

Deadly androgen-independent prostate cancers continue to rely on expression of the androgen receptor, which is supported by a specific isoform of transcription factor NFB. (Source: Cancer Research)

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Ozarelix, a fourth generation GnRH antagonist, induces apoptosis in hormone refractory androgen receptor negative prostate cancer cells modulating expression and activity of death receptors

The Prostate — Sun, 04 Apr 2010 23:00:00 +0100

This study explored the in vitro effects on DU145 and PC3 cell lines, two models of androgen-independent prostate cancer, of a fourth generation GnRH antagonist (Ozarelix).Ozarelix was added to cultures and toxicity, cell cycle modifications, cell viability and caspase activity were investigated.Ozarelix showed antiproliferative effects and produced an accumulation of cells in G2/M cell cycle phase. Apoptosis was related with caspase-8-dependent caspase 3 activation with down-regulation of c-FLIP (L) and a sensitization to TRAIL-induced apoptosis linked also to increased expression and activity of death receptors DR4/5 and Fas.TRAIL-resistant cancer cells can be sensitized to TRAIL by Ozarelix. This effect may be achieved by the activation of apoptotic pathway improving the therapeutic eff...

The synthetic estrogen diethylstilbestrol (DES) inhibits the telomerase activity and gene expression of prostate cancer cells

The Prostate — Sun, 04 Apr 2010 23:00:00 +0100

Telomerase, which lengthens telomeres, is normally down-regulated in somatic cells and highly up-regulated in dividing cells, such as malignant cells. Human prostate cancer is androgen dependent. Estrogens, including the synthetic estrogen diethylstilbestrol (DES), are used in prostate cancer treatment to reduce androgen levels via feedback inhibition of the hypothalamic release of luteinizing hormone releasing hormone (LH-RH). DES has also direct anticancer activities, such as apoptosis induction. We investigated in vitro the effect of DES on telomerase activity and on gene expression in the presence and absence of androgens. We used two prostate cancer cell lines: LNCaP (androgen dependent) and PC3 (androgen independent).LNCaP and PC3 cells were treated with 0.1-1,000 nM testosterone or ...

895 pretreatment psa growth pattern predicts early death after chemotherapy in patients with androgen-independent prostate cancer

European Urology Supplements — Mon, 29 Mar 2010 15:06:19 +0100

(Source: European Urology Supplements)

901 somatostatin analog in the treatment of androgen-independent prostate cancer before and after chemotherapy

European Urology Supplements — Mon, 29 Mar 2010 15:06:19 +0100

(Source: European Urology Supplements)

685 predictors of the risk of androgen-independent progression after salvage radical prostatectomy for locally recurrent prostate cancer following initial radiation therapy

European Urology Supplements — Mon, 29 Mar 2010 15:06:03 +0100

(Source: European Urology Supplements)

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662 simvastatin induces apoptosis in androgen-independent prostate cancer through a nuclear factor-κb-dependent mechanism

European Urology Supplements — Mon, 29 Mar 2010 15:06:02 +0100

(Source: European Urology Supplements)

Effect of Ack1 tyrosine kinase inhibitor on ligand-independent androgen receptor activity

The Prostate — Sat, 27 Mar 2010 00:00:00 +0100

Androgen receptor (AR) plays a critical role in the progression of both androgen-dependent and androgen-independent prostate cancer (AIPC). Ligand-independent activation of AR in AIPC or castration resistant prostate cancer (CRPC) is often associated with poor prognosis. Recently, tyrosine kinase Ack1 has been shown to regulate AR activity by phosphorylating it at tyrosine 267 and this event was shown to be critical for AIPC growth. However, whether a small molecule inhibitor that can mitigate Ack1 activation is sufficient to abrogate AR activity on AR regulated promoters in androgen-depleted environment is not known.We have generated two key resources, antibodies that specifically recognize pTyr267-AR and synthesized a small molecule inhibitor of Ack1, 4-amino-5,6-biaryl-furo[2,3-d]pyrimi...

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)

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)

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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...

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...

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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...

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...

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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...

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)