Novel Roles of STUB1 in Resistant Prostate Cancer
Abstract
Androgen-deprivation therapy or castration became standard practice for prostate cancer. However, eventually prostate cancer escapes its response to castration, progresses, and results in death. Through androgen deprivation therapy, patients live longer, but ultimately die from castration-resistant prostate cancer (CRPC). There has been a major focus on the androgen receptor (AR) pathway as the principal therapeutic target for CRPC, including recently approved therapies such as next-generation antiandrogen enzalutamide and abiraterone. Despite these advances that provide temporary respite, almost all patients will go on to die from progressive and resistant prostate cancer. Therefore, there is an urgent need to identify and target resistant pathways that perpetuate disease progression during an effective AR blockade. Considerable evidence from both clinical and experimental studies demonstrated that androgen receptor variant 7 (AR-V7) plays a vital role in induction of resistance to enzalutamide and abiraterone therapy. Emerging evidence suggests proteomic equilibrium may be altered during tumorigenesis, which consequently leads to protein homeostasis (proteostasis) deficiency and oncogenic activation at the protein level. However, the role of proteostasis involved in resistance to next-generation anti-androgens is still unknown. We have determined that the imbalance of proteostasis induced by Enza/Abi treatment in CRPC cells may be one of the critical mechanisms conferring drug resistance. This proposal will fill the gap in understanding the mechanisms of protein post-translational regulation in anti-androgen-resistant CRPC and in finding strategies to correct the proteostasis imbalance. We identified that the STUB1/HSP70 complex binds AR/AR-V7 in resistant CRPC cells and is involved in AR and AR variants stabilization and protein expression. Inhibition of HSP70 sensitizes AR targeted therapies by regulating AR-V7 expression. Clinically, HSP70 level is correlated with AR and AR-V7 in high Gleason score prostate tumors, suggesting that HSP70 may serve as a potential marker to indicate CRPC progression and therapeutic resistance. Additionally, we provide a proof-of-concept study that shows that targeting HSP70 could be a valuable strategy to treat AR-V7 overexpressing CRPC. This proposal aims to understand how the chaperone-ubiquitin-proteasome system contributes to next-generation anti-androgen resistance and to find strategies to overcome this resistance. This proposed study will address the PCRP Overarching Challenge to “Develop treatments that improve outcomes for men with lethal prostate cancer.” Successful completion of this proposal will help us to better understand how the chaperone-ubiquitin-proteasome system mediated by STUB1/HSP70 contributes to next-generation anti-androgen resistance and find strategies to overcome this resistance. It will provide a rationale for targeting proteostasis through inhibition of HSP70 as a potential therapeutic strategy for CRPC patients resistant to AR-targeted therapies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910843
Entities
People
- Allen Gao
Organizations
- United States Army
- University of California, Davis