Abstract

Protein homeostasis (proteostasis) is a potential mechanism that contributes to cancer cell survival and drug resistance. Constitutively active androgen receptor (AR) variants confer anti-androgen resistance in advanced prostate cancer. However, the role of proteostasis involved in next generation anti-androgen resistance and the mechanisms of AR variant regulation are poorly defined. Here we show that the ubiquitin-proteasome-system (UPS) is suppressed in enzalutamide/abiraterone resistant prostate cancer. AR/AR-V7 proteostasis requires the interaction of E3 ubiquitin ligase STUB1 and HSP70 complex. STUB1 disassociates AR/AR-V7 from HSP70, leading to AR/AR-V7 ubiquitination and degradation. Inhibition of HSP70 significantly inhibits prostate tumor growth and improves enzalutamide/abiraterone treatments through AR/AR-V7 suppression. Clinically, HSP70 expression is upregulated and correlated with AR/AR-V7 levels in high Gleason score prostate tumors. Our results reveal a novel mechanism of anti-androgen resistance via UPS alteration which could be targeted through inhibition of HSP70 to reduce AR-V7 expression and overcome resistance to AR-targeted therapies.

Details

Title
Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer
Author
Liu, Chengfei 1 ; Wei, Lou 1 ; Yang, Joy C 1 ; Liu, Liangren 2 ; Armstrong, Cameron M 1 ; Lombard, Alan P 1 ; Zhao, Ruining 3 ; Noel, Onika D V 1 ; Tepper, Clifford G 4   VIAFID ORCID Logo  ; Hong-Wu, Chen 5 ; Marc Dall’Era 6 ; Evans, Christopher P 6 ; Gao, Allen C 7 

1  Department of Urology, University of California Davis, Davis, CA, USA 
2  Department of Urology, West China Hospital, Sichuan University, Chengdu, China 
3  Department of Urology, General Hospital of Ningxia Medical University, Yinchuan, China 
4  Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, CA, USA; UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA, USA 
5  Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, CA, USA; UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA, USA; VA Northern California Health Care System, Sacramento, CA, USA 
6  Department of Urology, University of California Davis, Davis, CA, USA; UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA, USA 
7  Department of Urology, University of California Davis, Davis, CA, USA; UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA, USA; VA Northern California Health Care System, Sacramento, CA, USA 
Pages
1-16
Publication year
2018
Publication date
Nov 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-07178-x
ProQuest document ID
2134280449
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.