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.
Highlights
These authors contributed : Jianfu Zhou, Yuliang WangProstate cancer is the most frequently diagnosed malignancy among males in majority of economically developed countries, and is the second most common cancer in men worldwide [1, 2]
ERRα is characterized to increase the local estrogen production by up-regulating aromatase (CYP19A1) expression in response to prostaglandin E2 in prostate stromal cells [68]. These findings suggest that ERRα can modulate the intracellular steroidogenic capacity, which prompts us to determine the functional roles of ERRα in intratumoral androgen biosynthesis in prostate cancer
Some key steroidogenic enzymes, which are upregulated in castrationresistant prostate cancer (CRPC) and supporting the relapse growth of CRPC, have become the emerging therapeutic targets for CRPC with a therapeutic purpose to reduce the intraprostatic androgen levels
Summary
Prostate cancer is the most frequently diagnosed malignancy among males in majority of economically developed countries, and is the second most common cancer in men worldwide [1, 2]. Recent studies from us and other group show that the ONRs can contribute to the castration-resistant growth of prostate cancer through their promotion of intratumoral androgen biosynthesis via front-door and/or backdoor pathways by their transcriptional regulation of multiple key steroidogenic enzyme genes [23, 40, 41]. Our recent study shows that LRH-1 displays an increased expression pattern in clinical CRPC tissues, CRPC xenograft models, and abiraterone-treated CRPC tumors, and its overexpression can promote both in vitro androgen deprivation-resistant and in vivo castration-resistant growth capacities in ARpositive prostate cancer cells via its direct transactivation of multiple key steroidogenic enzyme genes (including STAR, CYP11A1, HSD3B2, CYP17A1) and enhanced intratumoral [36] [37] [38] [39, 40] [41] [23] [42]
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