Androgen Receptor Is a Potential Therapeutic Target for Bladder Cancer

Wu, Jitao; Han, Bangmin; Yu, Shengqiang; Wang, Huiping; Xia, Shujie

doi:10.1016/j.urology.2009.10.041

Cited by 74 publications

(60 citation statements)

References 24 publications

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“…We and others have documented that AR signals have stimulatory effects on bladder cancer cell proliferation (Miyamoto et al 2007, Johnson et al 2008, Boorjian et al 2009, Wu et al 2010, Zheng et al 2011. Dysregulation of the Wnt/b-catenin signaling pathway has also been linked to bladder cancer growth (Bui et al 1998, Shiina et al 2002, Hsieh et al 2004, Stoehr et al 2004, Urakami et al 2006, Kastritis et al 2009, Hirata et al 2012).…”

Section: Discussionmentioning

confidence: 97%

“…The c-MYC gene has indeed been found to correlate with the proliferation of bladder cancer cells (Lipponen 1995, Schmitz-Drager et al 1997. Androgen/AR-mediated upregulation of other Wnt targets, including cyclin-D1 (Wu et al 2010) and EGFR (Zheng et al 2011), has also been demonstrated in bladder cancer cells. Furthermore, using immunofluorescence and western blotting, we validated AR-induced nuclear translocation of b-catenin, which has been investigated in several other types of cells (Mulholland et al 2002, Pawlowski et al 2002, Yang et al 2002, Singh et al 2006, in bladder cancer cells with endogenous or exogenous AR.…”

Section: Discussionmentioning

confidence: 99%

“…AR signals have been implicated in bladder carcinogenesis and tumor progression. Specially, promising evidence further documents a critical role of AR in bladder cancer cell proliferation (Miyamoto et al 2007, Johnson et al 2008, Boorjian et al 2009, Wu et al 2010, Zheng et al 2011. Nonetheless, the mechanism by which AR signaling modulates bladder cancer progression remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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Androgen activates β-catenin signaling in bladder cancer cells

Zheng

Izumi

et al. 2013

Endocrine-Related Cancer

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Androgen receptor (AR) signals have been implicated in bladder carcinogenesis and tumor progression. Activation of Wnt/b-catenin signaling has also been reported to correlate with bladder cancer progression and poor patients' outcomes. However, cross talk between AR and b-catenin pathways in bladder cancer remains uncharacterized. In radical cystectomy specimens, we immunohistochemically confirmed aberrant expression of b-catenin especially in aggressive tumors. There was a strong association between nuclear expressions of AR and b-catenin in bladder tumors (PZ0.0215). Kaplan-Meier and log-rank tests further revealed that reduced membranous b-catenin expression (PZ0.0276), nuclear b-catenin expression (PZ0.0802), and co-expression of nuclear AR and b-catenin (PZ0.0043) correlated with tumor progression after cystectomy. We then assessed the effects of androgen on b-catenin in AR-positive and AR-negative bladder cancer cell lines. A synthetic androgen R1881 increased the expression of an active form of b-catenin and its downstream target c-myc only in AR-positive lines. R1881 also enhanced the activity of b-catenin-mediated transcription, which was abolished by an AR antagonist hydroxyflutamide. Using western blotting and immunofluorescence, R1881 was found to induce nuclear translocation of b-catenin when co-localized with AR. Finally, co-immunoprecipitation revealed androgeninduced associations of AR with b-catenin or T-cell factor (TCF) in bladder cancer cells. Thus, it was likely that androgen was able to activate b-catenin signaling through the AR pathway in bladder cancer cells. Our results also suggest that activation of b-catenin signaling possibly via formation of AR/b-catenin/TCF complex contributes to the progression of bladder cancer, which may enhance the feasibility of androgen deprivation as a potential therapeutic approach.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Androgen activates β-catenin signaling in bladder cancer cells

Zheng

Izumi

et al. 2013

Endocrine-Related Cancer

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“…ARN-509, isolated using structure activity-relationship (SAR)-guided medical chemistry as a non-steroidal antiandrogen that retains full antagonist activity, has the structure similar to enzalutamide but greater in vivo activity in CRPC xenograft models [64]. In prostate cancer cells overexpressing AR, ARN-509 binds to the AR with 7-to 10-fold greater affinity than bicalutamide and inhibits AR nuclear translocation and DNA binding leading to tumor regression and apoptosis [64].…”

Section: Arn-509mentioning

confidence: 99%

“…In prostate cancer cells overexpressing AR, ARN-509 binds to the AR with 7-to 10-fold greater affinity than bicalutamide and inhibits AR nuclear translocation and DNA binding leading to tumor regression and apoptosis [64]. Similarly to enzalutamide that could induce seizure in animals by an off-target mechanism, ARN-509 was found in vitro to inhibit GABA-A currents.…”

Section: Arn-509mentioning

confidence: 99%

Dehydroepiandrosterone Derivatives as Potent Antiandrogens with Marginal Agonist Activity

Miyata¹

2015

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE May 2015 REPORT TYPEFinal Annual Summary PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERJohn s Hopkins Uni versity 600 N. Wolfe Street Baltimore, Maryland 21287 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTWe hypothesized that dehydroepiandrosterone metabolites or their synthetic derivatives are able to bind to the androgen receptor with low, if any, agonist activity and thus function as better antiandrogens than currently available ones. We preliminarily identified three potential dehydroepiandrosterone derivatives with marginal androgenic activity. In this project, we assessed the effects of these compounds, in comparison with classic antiandrogens clinically used, on cell proliferation/apoptosis, cell migration/invasion, and prostate-specific antigen expression in prostate cancer lines in vitro as well as on tumor growth in animal models for prostate cancer and found their inhibitory effects on androgen-mediated tumor outgrowth. We further dissected molecular mechanisms of how such compounds suppress the progression of prostate cancer and found that they could alter androgen-mediated androgen receptor functions in prostate cancer cells. Importantly, these dehydroepiandrosterone derivatives were found to possess marginal agonist effects on the activity of androgen receptor. SUBJECT TERMS IntroductionAlthough antiandrogens that can block androgen action through the androgen receptor (AR) have been widely used for the treatment of prostate cancer, the majority of available agents possess agonist activity, resulting in increases in serum prostate-specific antigen (PSA) levels, known as the antiandrogen withdrawal syndrome [1,2]. In addition, we previously demonstrated that androstenediol, a physiological metabolite from dehydroepiandrosterone (DHEA) and a precursor of testosterone, has an ...

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Protective effects of ascorbic acid against the genetic and epigenetic alterations induced by 3,5‐dimethylaminophenol in AA8 cells

Chao

Erkekoğlu

Tseng

et al. 2014

J of Applied Toxicology

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Exposure to monocyclic aromatic alkylanilines (MAAs), namely 2,6-dimethylaniline (2,6-DMA), 3,5-dimethylaniline (3,5-DMA) and 3-ethylaniline (3-EA), was significantly and independently associated with bladder cancer incidence. 3,5-DMAP (3,5-dimethylaminophenol), a metabolite of 3,5-DMA, was shown to induce an imbalance in cytotoxicity cellular antioxidant/oxidant status, and DNA damage in mammalian cell lines. This study was designed to evaluate the protective effect of ascorbic acid (Asc) against the cytotoxicity, reactive oxygen species (ROS) production, genotoxicity and epigenetic changes induced by 3,5-DMAP in AA8 Chinese Hamster Ovary (CHO) cells. In different cellular fractions, 3,5-DMAP caused alterations in the enzyme activities orchestrating a cellular antioxidant balance, decreases in reduced glutathione levels and a cellular redox ratio as well as increases in lipid peroxidation and protein oxidation. We also suggest that the cellular stress caused by this particular alkylaniline leads to both genetic (Aprt mutagenesis) and epigenetic changes in histones 3 and 4 (H3 and H4). This may further cause molecular events triggering different pathological conditions and eventually cancer. In both cytoplasm and nucleus, Asc provided increases in 3,5-DMAP-reduced glutathione levels and cellular redox ratio and decreases in the lipid peroxidation and protein oxidation. Asc was also found to be protective against the genotoxic and epigenetic effects initiated by 3,5-DMAP. In addition, Asc supplied protection against the cell cycle (G1 phase) arrest induced by this particular alkylaniline metabolite.

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Androgen Receptor Is a Potential Therapeutic Target for Bladder Cancer

Cited by 74 publications

References 24 publications

Androgen activates β-catenin signaling in bladder cancer cells

Androgen activates β-catenin signaling in bladder cancer cells

Dehydroepiandrosterone Derivatives as Potent Antiandrogens with Marginal Agonist Activity

Protective effects of ascorbic acid against the genetic and epigenetic alterations induced by 3,5‐dimethylaminophenol in AA8 cells

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