After an initial response to androgen deprivation therapy (ADT) by depletion of gonadal testosterone, re-fueling androgen receptor in metastatic tumors is a critical mechanism required to drive castration resistant prostate cancer (CRPC) progression. Testosterone (T) is generally regarded as an obligate precursor for dihydrotestosterone (DHT) synthesis from adrenal precursors in CRPC and the up-regulation of steroid-5α-reductase isoenzyme-1 (SRD5A1) over SRD5A2 in CRPC is thought to convert T to DHT. Our recent findings demonstrated that an alternative pathway, namely androstenedione (AD) → 5α-androstanedione (5α-dione) → DHT, is dominant in CRPC. In this alternative pathway, AD prevails over T as a preferred substrate for 5α-reduction in CPRC. In particular, SRD5A1-mediated conversion of AD to 5α-dione is a prerequisite for converting adrenal steroids to DHT and for CRPC growth in mouse xenograft models. How 5α-dione is processed in CRPC is unknown. There are two possible routes from 5α-dione to DHT in the alternative pathway. The first route is direct 17-ketoreduction of 5α-dione by 17β-hydroxysteroid dehydrogenase-3 (17βHSD3) or 17βHSD5 (also known as aldo-keto reductase family 1, member C3, AKR1C3), both of which are up-regulated in CRPC progression. The second route is through a circuitous pathway, which requires 3-keto-reduction to 3α-hydroxyl, prior to 17-keto-reduction, namely 5α-dione → androsterone (AST) → 5α-androstane- 3α,17β-diol (Adiol) → DHT. Here, we show that ectopic expression of HSD17B5 in 293T cells efficiently converts 5α-dione to DHT, whereas AKR1C2 robustly catalyzes 5α-dione to AST and ultimately to DHT. This suggests that metabolism of 5α-dione may be determined by the relative expression and enzymatic activities of AKR1C3 and AKR1C2. These findings offer insights into the synthesis of DHT in CRPC and for the development of new therapeutic strategies.

Citation Format: Kai-Hsiung Chang, Amy Li, Nima Sharifi. Delineating the metabolic pathway to DHT in castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B2.