Orphan nuclear receptors as regulators of intratumoral androgen biosynthesis in castration-resistant prostate cancer

Abstract

Castration-resistant prostate cancer (CRPC) almost invariably occurs after androgen-deprivation therapy (ADT) for the advanced metastatic disease. It is generally believed that among multiple mechanisms and signaling pathways, CRPC is significantly driven by the reactivation of androgen receptor (AR) signaling in ADT-treated patients with castrate levels of androgen, partially at least mediated by the androgen biosynthesis within the tumor, also known as intratumoral or intraprostatic androgen biosynthesis. Steroidogenic enzymes, such as CYP11A1, CYP17A1, HSD3B1, AKR1C3 and SRD5A, are essential to catalyze the conversion of the initial substrate cholesterol into potent androgens that confers the CRPC progression. Accumulating evidences indicate that many steroidogenic enzymes are upregulated in the progression setting; however, little is known about the dysregulation of these enzymes in CRPC. Orphan nuclear receptors (ONRs) are members of the nuclear receptor superfamily, of which endogenous physiological ligands are unknown and which are constitutively active independent of any physiological ligands. Studies have validated that besides AR, ONRs could be the potential therapeutic targets for prostate cancer, particularly the lethal CRPC progression. Early studies reveal that ONRs play crucial roles in the transcriptional regulation of steroidogenic enzyme genes. Notably, we and others show that three distinct ONRs, including liver receptor homolog-1 (LRH-1, NR5A2), steroidogenic factor 1 (SF-1, AD4BP, NR5A1) and estrogen-related receptor α (ERRα, NR3B1), can contribute to the CRPC progression by promotion of the intratumoral androgen synthesis via their direct transcriptional regulation on multiple steroidogenic enzymes. This review presents an overview of the current understanding on the intratumoral androgen biosynthesis in CRPC, with a special focus on the emerging roles of ONRs in this process.

Fig. 1. Recognized pathways of androgen biosynthesis in prostate cancer.

Three potential pathways currently exist and function in CRPC that may confer increased levels of androgen biosynthesis within the tumor through the sequential actions of steroidogenic enzymes that are normally active in the testes and adrenal glands. Cholesterol is converted to pregnenolone by the action of STAR and CYP11A1. In the front-door (canonical or classical) pathway (greyish green), characterized by the necessity of testosterone (T) as an essential precursor that generate DHT, pregnenolone is converted to dehydroepiandrosterone (DHEA) by the sequential hydroxylase and lyase activity of CYP17A1. DHEA (from intrinsic or adrenal) is then acted on by HSD3B to yield androstenedione or by HSD17B3 (or AKR1C3) to yield androstenediol, which are subsequently converted to T, followed by its 5α-reduction to dihydrotestosterone (DHT) by 5α-reductases (SRD5As). On the other hand, the backdoor pathways refer to use of distinct substrates and enzymatic reactions to synthesize DHT bypassing T as intermediate. In the primary backdoor pathway (pink), the progesterone intermediates are 5α- and 3α-reduced by SRD5As and AKR1C2 before the lyase activity of CYP17A1, forming the androsterone and then to androstanediol by HSD17Bs (or AKR1C3) to generate DHT. In the secondary backdoor (5α-Adione) pathway (yellow), androstenedione as produced in the classical pathway is converted to 5α-androstenedione (5α-Adione) by SRD5As instead of conversion to T, and then to DHT by HSD17Bs (or AKR1C3). The necessary steroidogenic enzymes (gene names) catalyzing different steps of androgen biosynthesis are colour-coded across the three pathways. (STAR = steroidogenic acute regulatory protein; CYP11A1 = cholesterol side-chain cleavage enzyme; CYP17A1 = steroid 17α-monooxygenase; AKR1C3 = aldo-keto reductase 1C3; HSD17Bs = 17B-hydroxysteroid dehydrogenases; HSD3Bs = 3β-hydroxysteroid dehydrogenases; SRD5As = steroid 5α-reductase; AKR1C2 = aldo-keto reductase 1C2.).

Fig. 2. Schematic diagram illustrates the specific roles of ERRα, LRH-1, and SF-1 in the regulation of key enzymatic genes involved in intratumoral androgen biosynthesis in prostate cancer cells.

Multiple key enzymatic genes involved in distinct pathways of androgen biosynthesis can be transcriptionally activated by ERRα, LRH-1, and SF-1; and their transactivations contribute to the increase of intratumoral androgen concentration in prostate cancer cells, resulting in activation of AR signaling and thus fueling the castration-resistant growth of prostate cancer cells.