AKR1C3 Promotes AR-V7 Protein Stabilization and Confers Resistance to AR-Targeted Therapies in Advanced Prostate Cancer
Abstract
The mechanisms resulting in resistance to next-generation antiandrogens in castration-resistant prostate cancer are incompletely understood. Numerous studies have determined that constitutively active androgen receptor (AR) signaling or full-length AR bypass mechanisms may contribute to the resistance. Previous studies established that AKR1C3 and AR-V7 play important roles in enzalutamide and abiraterone resistance. In the present study, we found that AKR1C3 increases AR-V7 expression in resistant prostate cancer cells through enhancing protein stability via activation of the ubiquitin-mediated proteasome pathway. AKR1C3 reprograms AR signaling in enzalutamide-resistant prostate cancer cells. In addition, bioinformatical analysis of indomethacin-treated resistant cells revealed that indomethacin significantly activates the unfolded protein response, p53, and apoptosis pathways, and suppresses cell-cycle, Myc, and AR/ARV7 pathways. Targeting AKR1C3 with indomethacin significantly decreases AR/AR-V7 protein expression in vitro and in vivo through activation of the ubiquitin-mediated proteasome pathway. Our results suggest that the AKR1C3/AR-V7 complex collaboratively confers resistance to AR-targeted therapies in advanced prostate cancer.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 01, 2019
- Source ID
- 10.1158/1535-7163.mct-18-1322
Entities
People
- Alan P. Lombard
- Allen C Gao
- Binhao Zou
- Cameron M. Armstrong
- Chengfei Liu
- Christopher P Evans
- Joy C. Yang
- Leandro S. D’Abronzo
- Liangren Liu
- Wei Lou
- Xiaomin Qiu
Organizations
- United States Department of Defense
- University of California
- University of California, Davis
- Veterans Health Administration Office of Research and Development