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.