Advances in the Current Understanding of the Mechanisms Governing the Acquisition of Castration-Resistant Prostate Cancer

Abstract

Despite aggressive treatment and androgen-deprivation therapy, most prostate cancer patients ultimately develop castration-resistant prostate cancer (CRPC), which is associated with high mortality rates. However, the mechanisms governing the development of CRPC are poorly understood, and androgen receptor (AR) signaling has been shown to be important in CRPC through AR gene mutations, gene overexpression, co-regulatory factors, AR shear variants, and androgen resynthesis. A growing number of non-AR pathways have also been shown to influence the CRPC progression, including the Wnt and Hh pathways. Moreover, non-coding RNAs have been identified as important regulators of the CRPC pathogenesis. The present review provides an overview of the relevant literature pertaining to the mechanisms governing the molecular acquisition of castration resistance in prostate cancer, providing a foundation for future, targeted therapeutic efforts.

Keywords: Hh pathway; Wnt pathway; androgen receptor; destructive resistance prostate cancer; ncRNAs.

Figure 1

Structural overview of ARs and AR-Vs (AR-V3,7,9 and ARv567es). (A) Structural overview of the AR gene, located on the X chromosome q11-q12, encoding 919 amino acids and consisting of eight exons. The DHT and T ligands to the AR LBD; (B) The mechanisms underlying AR-V3, AR-V7, and AR-V9 production. Exons 4–8 are sheared to produce truncated AR-Vs that lack a LBD and Hinge region; (C) Mechanisms governing the production of ARv567es. Exons 5–7 are missing, resulting in truncated AR proteins and the lack of a LBD. AR = Androgen receptor; AR-Vs = AR variants; NTD  =  N-terminal transcriptional domain; DBD  =  DNA-binding domain; LBD  =  C-terminal ligand-binding domain; CE5  =  cryptic exon 5; CE3  =  cryptic exon 3; PAS  =  polyadenylation site; CE4  =  cryptic exon.

Figure 2

Mechanisms governing the progression of prostate cancer to castration-resistant prostate cancer (CRPC). T: Testosterone; DHT: Dihydrotestosterone; AR: Androgen receptor; AR-Vs: AR variants; DHEA: Dehydroepiandrosterone; A2: androstenedione; 11OXHA4: 11-oxygenated androgens; 11KT: 11-ketotestosterone; 11KDHT: 11-ketodihydrotestosterone.