| Literature DB >> 31308078 |
Chengfei Liu1, Joy C Yang1, Cameron M Armstrong1, Wei Lou1, Liangren Liu1, Xiaomin Qiu1, Binhao Zou1, Alan P Lombard1, Leandro S D'Abronzo1, Christopher P Evans1,2, Allen C Gao3,2,4.
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. ©2019 American Association for Cancer Research.Entities:
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Year: 2019 PMID： 31308078 PMCID： PMC6995728 DOI： 10.1158/1535-7163.MCT-18-1322
Source DB: PubMed Journal: Mol Cancer Ther ISSN： 1535-7163 Impact factor: 6.261