Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer

Abstract

In the majority of cases, advanced prostate cancer responds initially to androgen deprivation therapy by depletion of gonadal testosterone. The response is usually transient, and metastatic tumors almost invariably eventually progress as castration-resistant prostate cancer (CRPC). The development of CRPC is dependent upon the intratumoral generation of the potent androgen, dihydrotestosterone (DHT), from adrenal precursor steroids. Progression to CRPC is accompanied by increased expression of steroid-5α-reductase isoenzyme-1 (SRD5A1) over SRD5A2, which is otherwise the dominant isoenzyme expressed in the prostate. DHT synthesis in CRPC is widely assumed to require 5α-reduction of testosterone as the obligate precursor, and the increased expression of SRD5A1 is thought to reflect its role in converting testosterone to DHT. Here, we show that the dominant route of DHT synthesis in CRPC bypasses testosterone, and instead requires 5α-reduction of androstenedione by SRD5A1 to 5α-androstanedione, which is then converted to DHT. This alternative pathway is operational and dominant in both human CRPC cell lines and fresh tissue obtained from human tumor metastases. Moreover, CRPC growth in mouse xenograft models is dependent upon this pathway, as well as expression of SRD5A1. These findings reframe the fundamental metabolic pathway that drives CRPC progression, and shed light on the development of new therapeutic strategies.hormonal therapy | 5-alpha-androstanedione | tumor metabolism | abiraterone acetate | hormone resistance

Influence of dioxin exposure upon levels of prostate-specific antigen and steroid hormones in Vietnamese men

“…The Physicians' Health Study confirmed the starting hypothesis, namely that testosterone and dihydrotestosterone (DHT) were positively associated with estradiol, and that sex hormone binding globulin was inversely associated with prostate cancer (Gann PH et al 1996). In recent years, several clinical studies of hormone treatment for prostate cancer have been done (Cai C et al 2011;Chang KH et al 2011;Mostaghel EA et al 2011;Richards J et al 2012;Mostaghel EA 2013). Prostate-specific antigen (PSA) is a glycoprotein produced almost exclusively by the epithelial cells of the prostate gland, and is used as a marker for the diagnosis and monitoring of prostate cancer (Hudson MA et al 1989;Oesterling JE 1991;Armbruster DA 1993).…”

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

“…3β-HSD is expressed in the normal human prostate, with immunoblotting revealing that the highest concentrations are found in basal epithelial cells (Luu-The et al 2008). Certainly, in mouse xenograft studies using the CRPC LAPC4 cell line, expression of 3β-HSD is increased within the tumour in addition to AKR1C3 and 17β-HSD3 (Chang et al 2011), although its mRNA expression almost completely mutually excludes that of CYP19A1 (Hofland et al 2010).…”

“…Mass spectrometry has shown that even in patients on anti-androgen therapy with very low serum testosterone levels, intra-tumoural DHT concentrations remain at the pre-treatment level (Chang et al 2011. 17β-HSD-5, also known as AKR1C3, appears to be the key enzyme responsible for intra-tumoural androgen production in CRPC.…”

Understanding the diversity of sex steroid action

“…E 1 ) to highly active 17b-steroids (e.g. E 2 ), and vice versa, has also become apparent, and the enzymes are expected to be involved in the local production of both classical and novel ligands for ERs in several normal and diseased tissues (for example, Chang et al 2011, Mohler et al 2011, Saijo et al 2011, Saloniemi et al 2012. It is thus likely that yet unknown endogenous small molecular compounds modulating ERs are to be discovered in the future.…”