Classical and Non-Classical Roles for Pre-Receptor Control of DHT Metabolism in Prostate Cancer Progression

Abstract

Androgens play an important role in prostate cancer (PCa) development and progression. Accordingly, androgen deprivation therapy remains the front-line treatment for locally recurrent or advanced PCa, but patients eventually relapse with the lethal form of the disease termed castration resistant PCa (CRPC). Importantly, castration does not eliminate androgens from the prostate tumor microenvironment which is characterized by elevated tissue androgens that are well within the range capable of activating the androgen receptor (AR). In this mini-review, we discuss emerging data that suggest a role for the enzymes mediating pre-receptor control of dihydrotestosterone (DHT) metabolism, including AKR1C2, HSD17B6, HSD17B10, and the UGT family members UGT2B15 and UGT2B17, in controlling intratumoral androgen levels, and thereby influencing PCa progression. We review the expression of steroidogenic enzymes involved in this pathway in primary PCa and CRPC, the activity and regulation of these enzymes in PCa experimental models, and the impact of genetic variation in genes mediating pre-receptor DHT metabolism on PCa risk. Finally, we discuss recent data that suggests several of these enzymes may also play an unrecognized role in CRPC progression separate from their role in androgen inactivation.

Fig. 1

Pre-receptor control of DHT metabolism in prostate (dashed square). Both reducing and conjugating DHT catabolizing enzymes together with DHT oxidases regulate intracellular levels of DHT and hereby, its access to the androgen receptor (AR). AKR1C2 catalyzes the reversible reduction of DHT to 3α-diol. HSD17B6 (RL-HSD), HSD17B10, and RDH5 oxidize 3α-diol back to DHT. The activities of both reductive 3α-HSDs and oxidative 3α-HSDs determine the intracellular levels of DHT. HSD17B6 also converts physiological concentration of DHT to 3β-diol. AKR1C1 catalyzes the irreversible conversion of DHT to 3β-diol. UGT2B28, UGT2B17, and UGT2B15 are all involved of glucuronidation of androgen metabolites; UGT2B15 and UGT2B17 can also directly glucuronidate DHT (not shown)

Fig. 2

Altered pre-receptor metabolism of DHT in prostate cancer progression. a Schematic of androgen synthesis and pre-receptor control of DHT metabolism in normal prostate tissue. b Differential changes in steroidogenic enzymes in primary prostate cancer vs normal prostate tissue: increased tumor expression of reductive enzymes HSD17B3 and AKR1C3 and decreased expression of the oxidative enzyme HSD17B2, favoring production of active androgens from inactive diones; a decrease in tumoral SRD5A2 and increase in SRD5A1; and decreased expression of both AKR1C2 and AKR1C1 with increased expression of HSD17B10, favoring production of DHT. Expression of HSD17B6 is low in untreated primary PCa, but increased in men treated with androgen deprivation (upward arrow with*). c Altered expression of genes mediating DHT production and catabolism in CRPC: variably increased expression of STAR, CYP17A, and HSD3β2, involved in de novo steroid synthesis; consistently increased expression of AKR1C3 and SRD5A1, mediating conversion of adrenal androgens to downstream steroids; paradoxical increase in expression of genes involved in DHT catabolism including AKR1C1, AKR1C2, and UGT2B15 and 17; and increased expression of HSD17B10 in conjunction with increased AKR1C2, suggesting activity via a testosterone bypass pathway (thick arrows) with steroid flux directed to DHT via androstanedione, androsterone, and 3α-diol. (Upward arrows denote increased gene expression, and downward arrows denote decreased gene expression)