Abstract
Protein homeostasis (proteostasis) is a potential mechanism that contributes to cancer cell survival and drug resistance. Constitutively active androgen receptor (AR) variants confer anti-androgen resistance in advanced prostate cancer. However, the role of proteostasis involved in next generation anti-androgen resistance and the mechanisms of AR variant regulation are poorly defined. Here we show that the ubiquitin-proteasome-system (UPS) is suppressed in enzalutamide/abiraterone resistant prostate cancer. AR/AR-V7 proteostasis requires the interaction of E3 ubiquitin ligase STUB1 and HSP70 complex. STUB1 disassociates AR/AR-V7 from HSP70, leading to AR/AR-V7 ubiquitination and degradation. Inhibition of HSP70 significantly inhibits prostate tumor growth and improves enzalutamide/abiraterone treatments through AR/AR-V7 suppression. Clinically, HSP70 expression is upregulated and correlated with AR/AR-V7 levels in high Gleason score prostate tumors. Our results reveal a novel mechanism of anti-androgen resistance via UPS alteration which could be targeted through inhibition of HSP70 to reduce AR-V7 expression and overcome resistance to AR-targeted therapies.
Highlights
Protein homeostasis is a potential mechanism that contributes to cancer cell survival and drug resistance
To understand the potential mechanisms that may be involved in overexpression of androgen receptor (AR)-V7 protein in enzalutamide-resistant cells, we determined whether AR-V7 protein stabilization was altered in C4-2B MDVR cells
The results suggest that AR-V7 is overexpressed in resistant prostate cancer cells via enhanced protein stability through ubiquitin proteasome system alteration
Summary
Protein homeostasis (proteostasis) is a potential mechanism that contributes to cancer cell survival and drug resistance. Enzalutamide and abiraterone are the second-generation antiandrogen drugs approved for the treatment of castration-resistant prostate cancer (CRPC). The chaperone protein family, including heat shock proteins (HSPs), regulates the activity and stability of many oncogenes that control cancer cell survival and progression[3,13,14,15]. We discover that the ubiquitin-mediated proteolysis pathway and proteasome activity are suppressed in enzalutamide and abiraterone-resistant prostate cancer cells which stabilizes AR-V7 protein in these cells through ubiquitin–proteasome alteration. The levels of HSP70 are correlated with AR-V7 in tumors from patients with high Gleason scores These results suggest that targeting the proteostasis pathway through inhibiting HSP70 might be a valuable strategy to overcome generation anti-androgen resistance and improve drug therapy in CRPC patients
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