Androgen action and metabolism in prostate cancer

Abstract

The transcriptional programs regulated through the activity of the androgen receptor (AR) modulate normal prostate development and the maintenance of prostatic functions at maturity. AR signaling also controls key survival and growth functions operative in prostate cancer. Inhibiting the AR program remains the key target in the treatment of advanced prostate cancer, and suppressing AR also holds great potential for preventing the development or progression of early stage prostate cancer. In this review, we detail molecular mechanisms of AR activity, cellular components contributing to the maintenance of AR signaling despite AR-ligand suppression, and discuss treatment strategies designed to target components of resistance to AR-directed therapeutics.

Figure 1. Androgen receptor domains affected by mutation in prostate cancer and exon structure of major splice variants

(A) Domains of the full length androgen receptor (AR), include the amino (N) terminal domain (NTD), the DNA binding domain (DBD), the hinge region (HR) and the carboxy (C) terminal ligand binding domain (LBD), involved in the indicated functions in AR transactivation. Three codon regions of the AR in which mutations have been identified in prostate tumors are denoted, along with the indicated changes in function. Generation of recently reported truncated AR variants lacking the LBD occurs via alternative splicing to cryptic exons (B, C), or alternative splicing with exon skipping, resulting in exon deletion (D). In all cases the N’ terminal domain is lost, with consequent loss of ligand binding activity.

Figure 2. The classical and backdoor pathways of androgen biosynthesis

In the classical pathway (solid gray arrow), C21 precursors (pregnenolone and progesterone) are converted to the C19 adrenal androgens DHEA and androstenedione (AED) by the sequential hydroxylase and lyase activity of CYP17A1. Circulating adrenal androgens (including the sulfated form of DHEA, DHEA-S), enter the prostate and can be converted to testosterone by a series of reactions involving the activity of HSD3B, HSD17B and AKR1C enzymes. Testosterone is then converted to the potent androgen DHT by the activity of SRD5A. In the backdoor pathway to DHT synthesis (short gray arrows), C21 precursors are first acted upon by SRD5A and the reductive 3α-HSD activity of the AKR1C family member, AKR1C2, followed by conversion to C19 androgens via the lyase activity of CYP17A. DHT is subsequently generated by the action of HSD17B3 and an oxidative 3 α -HSD enzyme, including HSD17B6, HSD17B10 or HSD17B13 (as well as RODH4, RODH5 and NT 3 α-HSD, not shown). Adapted from Mostaghel EA, Nelson PS. Intracrine androgen metabolism in prostate cancer progression: mechanisms of castration resistance and therapeutic implications. Best Pract Res Clin Endocrinol Metab. 2008;22:243, with permission.