Mechanisms mediating androgen receptor reactivation after castration

Abstract

Androgen deprivation is still the standard systemic therapy for metastatic prostate cancer (PCa), but patients invariably relapse with a more aggressive form of PCa termed hormone refractory, androgen independent, or castration resistant PCa (CRPC). Significantly, the androgen receptor (AR) is expressed at high levels in most cases of CRPC, and these tumors resume their expression of multiple AR-regulated genes, indicating that AR transcriptional activity becomes reactivated at this stage of the disease. The molecular basis for this AR reactivation remains unclear, but possible mechanisms include increased AR expression, AR mutations that enhance activation by weak androgens and AR antagonists, increased expression of transcriptional coactivator proteins, and activation of signal transduction pathways that can enhance AR responses to low levels of androgens. Recent data indicate that CRPC cells may also carry out intracellular synthesis of testosterone and DHT from weak adrenal androgens and may be able to synthesize androgens from cholesterol. These mechanisms that appear to contribute to AR reactivation after castration are further outlined in this review.

Figure 1. AR activation in normal prostate/hormone naïve PCa and reactivation after androgen deprivation therapy

Androgen binding causes a conformational change in AR that results in dissociation from Hsp90, nuclear translocation, dimerization on androgen responsive elements (AREs) in androgen regulated genes, recruitment of steroid receptor coactivator proteins (SRC1–3), and recruitment of multiple other transcriptional coactivator proteins that acetylate histone (histone acetyltransferases, HATs) (CBP/p300, pCAF), methylate histones (CARM1), unwind DNA (SWI/SNF), or recruit the RNA polymerase II complex (TRAP220). AR activity is initially suppressed by androgen deprivation therapy (ADT), but the tumor cells eventually adapt by one or more mechanisms to reactivate AR activity, resulting in (or contributing to) the emergence of castration resistant prostate cancer (CRPC).

Figure 2. Androgen synthesis and metabolism in normal prostate and prostate cancer cells

The enzymes mediating testosterone and DHT synthesis from DHEA-S, DHEA, and androstenedione from precursor steroids are expressed in normal prostate, and many are increased in CRPC (HSD3B, AKR1C3, and SRD5A1), while SRD5A2 (the type 2 5α-reductase expressed at highest levels in normal prostate) is reduced. Enzymes mediating DHT catabolism are similarly increased, and CRPC cells may also express CYP17A1 (the enzyme inhibited by ketoconazole and abiraterone) and thereby synthesize androgens de novo from cholesterol.