AKR1C3 promotes AR-V7 protein stabilization and confers resistance to AR-targeted therapies in advanced prostate cancer

Chengfei Liu, Joy C. Yang, Cameron M. Armstrong, Wei Lou, Liangren Liu, Xiaomin Qiu, Binhao Zou, Alan P. Lombard, Leandro S. D'Abronzo, Christopher P. Evans, Allen C. Gao

Research output: Contribution to journalArticle


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.

Original languageEnglish (US)
Pages (from-to)1875-1886
Number of pages12
JournalMolecular Cancer Therapeutics
Issue number10
StatePublished - Jan 1 2019


ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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