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

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 3beta-hydroxysteroid dehydrogenase (3betaHSD) 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 3betaHSD metabolism is not required and that 3betaHSD 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 3betaHSD 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 3beta-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 3betaHSD. These findings demonstrate that DHEA and A5diol must be metabolized by 3betaHSD to activate AR in these models of CRPC. Furthermore, this work suggests that 3betaHSD may be exploited as a pharmacologic target in the treatment of CRPC.

Enhanced expression of organic anion transporting polypeptides (OATPs) in androgen receptor-positive prostate cancer cells: Possible role of OATP1A2 in adaptive cell growth under androgen-depleted conditions

“…These results suggest that DHEAS undergoes metabolism at least to DHEA, mediated by STS. DHEA thus generated may have a weak androgenic potential to activate AR directly, but is more likely converted to T or DHT via 3b-hydroxysteroid dehydrogenase (3bHSD), since cell proliferation of LNCaP cells in the presence of DHEA was reported to be suppressed by inhibition of 3bHSD [15]. Although DHEA is present in human serum (~ 5 nM), the DHEAS concentration in serum (3 ~ 5 μM) is almost a thousand fold greater [12]; therefore, DHEAS may be taken up by prostate cancer cells via OATPs as a source of DHEA to compensate for the shortage of androgen in serum.…”

“…DHEAS is a thousand fold more abundant than testosterone in human serum [12], and is essentially unaffected by ADT. DHEAS is hydrolyzed to DHEA by STS [13], and DHEA can be converted to androstenedione in prostate cancer [14], resulting in activation of AR function [15]. More recently, clinical observations have suggested that several OATPs are upregulated in castration-resistant metastatic prostate tumor tissues derived from human patients [16]; however, it remains unclear whether OATPs play a role in prostate cancer cell survival under androgen-depleted conditions.…”

Abiraterone Inhibits 3β-Hydroxysteroid Dehydrogenase: A Rationale for Increasing Drug Exposure in Castration-Resistant Prostate Cancer

“…DHT synthesis, either from adrenal precursors or via intratumoral de novo steroidogenesis from cholesterol, requires 3b-hydroxysteroid dehydrogenase/isomerase (3bHSD) enzymatic activity (16)(17)(18). Dehydroepiandrosterone (DHEA) and abi have structural similarities, in that both have a 3b-hydroxyl, D 5 -19-carbon steroid nucleus.…”

In touch with your feminine side: how oestrogen metabolism impacts prostate cancer

“…Inhibitors of 3β-HSD have been explored as an androgen deprivation technique as they are effective in decreasing proliferation in androgen-sensitive LNCaP or CRPC cell lines 22Rv1, VCaP and PC346C in vitro (Evaul et al 2010, Kumagai et al 2013. Furthermore, abiraterone was found to inhibit 3β-HSD activity in addition to CYP17A1 in prostate cancer cell lines and isolated yeast microsomes (Li et al 2012).…”