PT - JOURNAL ARTICLE AU - Liu, Chengfei AU - Yang, Joy C. AU - Armstrong, Cameron M. AU - Lou, Wei AU - Liu, Liangren AU - Qiu, Xiaomin AU - Zou, Binhao AU - Lombard, Alan P. AU - D'Abronzo, Leandro S. AU - Evans, Christopher P. AU - Gao, Allen C. TI - AKR1C3 Promotes AR-V7 Protein Stabilization and Confers Resistance to AR-Targeted Therapies in Advanced Prostate Cancer AID - 10.1158/1535-7163.MCT-18-1322 DP - 2019 Oct 01 TA - Molecular Cancer Therapeutics PG - 1875--1886 VI - 18 IP - 10 4099 - http://mct.aacrjournals.org/content/18/10/1875.short 4100 - http://mct.aacrjournals.org/content/18/10/1875.full SO - Mol Cancer Ther2019 Oct 01; 18 AB - 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.