RT Journal Article
SR Electronic
T1 AKR1C3 promotes AR-V7 protein stabilization and confers resistance to AR-targeted therapies in advanced prostate cancer
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP molcanther.1322.2018
DO 10.1158/1535-7163.MCT-18-1322
A1 Liu, Chengfei
A1 Yang, Joy C
A1 Armstrong, Cameron M.
A1 Lou, Wei
A1 Liu, Liangren
A1 Qiu, Xiaoming
A1 Zou, Binghao
A1 Lombard, Alan P.
A1 D'Abronzo, Leandro S
A1 Evans, Christopher P
A1 Gao, Allen C.
YR 2019
UL http://mct.aacrjournals.org/content/early/2019/07/13/1535-7163.MCT-18-1322.abstract
AB The mechanisms resulting in resistance to next generation anti-androgens in castration resistant prostate cancer are imcompletely 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. Additionally, bioinformatical analysis of indomethacin treated resistant cells revealed that indomethacin significantly activates the unfolded protein response (UPR), 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.