Abstract
BackgroundThe chemopreventive effects of resveratrol (RSV) on prostate cancer have been well established; the androgen receptor (AR) plays pivotal roles in prostatic tumorigenesis. However, the exact underlying molecular mechanisms about the effects of RSV on AR have not been fully elucidated. A model system is needed to determine whether and how RSV represses AR transcriptional activity.MethodologyThe AR cDNA was first cloned into the retroviral vector pOZ-N and then integrated into the genome of AR-negative HeLa cells to generate the AR(+) cells. The constitutively expressed AR was characterized by monitoring hormone-stimulated nuclear translocation, DNA binding, and transcriptional activation, with the AR(-) cells serving as controls. AR(+) cells were treated with RSV, and both AR protein levels and AR transcriptional activity were measured simultaneously. Chromatin immunoprecipitation (ChIP) assays were used to detect the effects of RSV on the recruitment of AR to its cognate element (ARE).ResultsAR in the AR (+) stable cell line functions in a manner similar to that of endogenously expressed AR. Using this model system we clearly demonstrated that RSV represses AR transcriptional activity independently of any effects on AR protein levels. However, neither the hormone-mediated nucleus translocation nor the AR/ARE interaction was affected by RSV treatment.ConclusionWe demonstrated unambiguously that RSV regulates AR target gene expression, at least in part, by repressing AR transcriptional activity. Repressive effects of RSV on AR activity result from mechanisms other than the affects of AR nuclear translocation or DNA binding.
Highlights
Prostate cancer is one of the biggest threats to men’s health in the western world and it accounts for the second largest number of male cancer deaths in the United States [1,2]
androgen receptor (AR) in the AR (+) stable cell line functions in a manner similar to that of endogenously expressed AR. Using this model system we clearly demonstrated that RSV represses AR transcriptional activity independently of any effects on AR protein levels
Neither the hormone-mediated nucleus translocation nor the AR/androgen responsive element (ARE) interaction was affected by RSV treatment
Summary
Prostate cancer is one of the biggest threats to men’s health in the western world and it accounts for the second largest number of male cancer deaths in the United States [1,2]. The best approach for combating prostate cancer is preventing its occurrence in the first place. High-grade prostatic intraepithelial neoplasia develops over a period of around twenty years, and the progression to clinically significant carcinoma may take another thirteen to fifteen years [5]. Since it usually takes some time for the chemopreventive effects to be observable, the long latency periods make prostate cancer one of the best model systems in chemoprevention studies [6]. A model system is needed to determine whether and how RSV represses AR transcriptional activity
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