3β-Hydroxysteroid Dehydrogenase Is a Possible Pharmacological Target in the Treatment of Castration-Resistant Prostate Cancer

Prostate cancer usually responds to androgen deprivation therapy, although the response in metastatic disease is almost always transient and tumors eventually progress as castration-resistant prostate cancer (CRPC). CRPC continues to be driven by testosterone or dihydrotestosterone from intratumoral metabolism of 19-carbon adrenal steroids from circulation, and/or de novo intratumoral steroidogenesis. Both mechanisms require 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) metabolism of Delta(5)-steroids, including dehydroepiandrosterone (DHEA) and Delta(5)-androstenediol (A5diol), to testosterone. In contrast, reports that DHEA and A5diol directly activate the androgen receptor (AR) suggest that 3 beta HSD metabolism is not required and that 3 beta HSD inhibitors would be ineffective in the treatment of CRPC. We hypothesized that activation of AR in prostate cancer by DHEA and A5diol requires their conversion via 3 beta HSD to androstenedione and testosterone, respectively. Here, we show that DHEA and A5diol induce AR chromatin occupancy and AR-regulated genes. Furthermore, we show that Delta(5)-androgens undergo 3 beta-dehydrogenation in prostate cancer and that induction of AR nuclear translocation, AR chromatin occupancy, transcription of PSA, TMPRSS2, and FKBP5, as well as cell proliferation by DHEA and A5diol, are all blocked by inhibitors of 3 beta HSD. These findings demonstrate that DHEA and A5diol must be metabolized by 3 beta HSD to activate AR in these models of CRPC. Furthermore, this work suggests that 3 beta HSD may be exploited as a pharmacologic target in the treatment of CRPC. (Endocrinology 151: 3514-3520, 2010)