3β-hydroxysteroid dehydrogenase is a possible pharmacological target in the treatment of castration-resistant prostate cancer

Kristen Evaul, Rui Li, Mahboubeh Papari-Zareei, Richard J. Auchus, Nima Sharifi

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

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 3β-hydroxysteroid dehydrogenase (3βHSD) metabolism of Δ5-steroids, including dehydroepiandrosterone (DHEA) and Δ5-androstenediol (A5diol), to testosterone. In contrast, reports that DHEA and A5diol directly activate the androgen receptor (AR) suggest that 3βHSD metabolism is not required and that 3βHSD 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 3βHSD to androstenedione and testosterone, respectively. Here, we show that DHEA and A5diol induce AR chromatin occupancy and AR-regulated genes. Furthermore, we show that Δ5-androgens undergo 3β-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 3βHSD. These findings demonstrate that DHEA and A5diol must be metabolized by 3βHSD to activate AR in these models of CRPC. Furthermore, this work suggests that 3βHSD may be exploited as a pharmacologic target in the treatment of CRPC.

Original languageEnglish (US)
Pages (from-to)3514-3520
Number of pages7
JournalEndocrinology
Volume151
Issue number8
DOIs
StatePublished - Aug 2010

ASJC Scopus subject areas

  • Endocrinology

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