The Crucial Role of AR-V7 in Enzalutamide-Resistance of Castration-Resistant Prostate Cancer

Abstract

Prostate cancer (PCa) has the second highest incidence of malignancies occurring in men worldwide. The first-line therapy of PCa is androgen deprivation therapy (ADT). Nonetheless, most patients progress to castration-resistant prostate cancer (CRPC) after being treated by ADT. As a second-generation androgen receptor (AR) antagonist, enzalutamide (ENZ) is the current mainstay of new endocrine therapies for CRPC in clinical use. However, almost all patients develop resistance during AR antagonist therapy due to various mechanisms. At present, ENZ resistance (ENZR) has become challenging in the clinical treatment of CRPC. AR splice variant 7 (AR-V7) refers to a ligand-independent and constitutively active variant of the AR and is considered a key driver of ENZR in CRPC. In this review, we summarize the mechanisms and biological behaviors of AR-V7 in ENZR of CRPC to contribute novel insights for CRPC therapy.

Keywords: AR-V7; LncRNA; castration-resistant prostate cancer; drug resistance; enzalutamide; proteostasis.

Figure 1

The Structure of AR-FL and AR-Vs. The human AR gene contains eight exons; AR has four domains, including NTD, DBD, HD and LBD. Exon 1 encodes NTD, DBD is encoded by exons 2 and 3, exon 4 encodes HD, and LBD is encoded by exons 5,6,78; AR-V7 has no LBD, so enzalutamide cannot bind to AR-V7; The DBD domain of AR-V3 is only encoded by exon 2, and lacks zinc finger; AR45 starts coding from exon 1b and lacks the NTD domain; The DBD domain formed by AR8 is only encoded by exon 3 and is not functional. AR8 inserts 69 nucleotides upstream of exon 3; AR-V567es does not contain exon 5.6.7; UTR: Untranslated Region; AR-FL: full-length androgen receptor; AR-V: androgen receptor splicing variant; NTD: N-end domain; DBD: DNA binding; HD: hinge domain; LBD: ligand binding domain; CE3: recessive exon 3; AF: Activate the function.

Figure 2

Enzalutamide acts on the AR signaling pathway. Enzalutamide binds to the LBD and blockades the AR signaling pathway by blocking the binding of androgens to AR, impeding the AR nuclear translocation, and inhibiting the AR transcriptional activity. AR-FL: full-length androgen receptor; AR-V7: androgen receptor splice variant 7; DHT: dihydrotestosterone. HSP: heat shock proteins.

Figure 3

Natural/compound drugs affect the transcriptional activity and protein stability of AR-V7 through the HSP family. ARVib, JG98, and C86 promote AR-V7 degradation by inhibiting HSP40/HSP70 axis; bruceantin promotes AR-V7 degradation by directly binding to HSP90 and disrupting the interaction between HSP90 and AR-V7; KRIBB3 promotes the degradation of AR by interacting with HSP27; niclosamide not only inhibits the transcriptional activity of AR-V7 but also promotes the degradation of AR-V7.