Protein disulfide isomerases regulate androgen receptor stability and promote prostate cancer cell growth and survival
Abstract
Cancer cells exhibit accelerated protein production to accommodate their high rates of growth and proliferation. Elevated protein synthesis creates a dependency on endoplasmic reticulum (ER)-resident proteins and chaperones, which are required to maintain proteostasis. In this study, we identified the protein disulfide isomerases (PDIs) PDIA1 and PDIA5, which play a critical role in folding of client proteins in the ER, as important regulators of prostate cancer growth and response to therapy. PDIA1 and PDIA5 are upregulated in prostate cancer and induced by the androgen receptor (AR) signaling axis. Genetic or pharmacological disabling of PDIA1/PDIA5 caused redox stress, mitochondrial dysfunction, growth inhibition, and death of prostate cancer cells in vitro and in vivo. The critical functions of these enzymes in redox homeostasis and cell survival were observed in both AR-driven and AR-independent models of prostate cancer. Loss of PDIA1/PDIA5 activity led to ubiquitination and degradation of the AR, revealing a feedback loop between these chaperones and the AR pathway. Mechanistically, PDIA1/PDIA5 regulated AR stability by mediating disulfide bond formation, an activity that required cysteines 669 and 844 in AR’s ligand-binding domain. Importantly, targeting PDIAs sensitized prostate cancer cells to the AR antagonist, enzalutamide. This study reveals a mechanism governing AR proteostasis in prostate cancer and positions PDIA1/5 as viable therapeutic targets.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (30)
Jianling Xie
School of Biology and Biological Engineering, South China University of Technology
Kaikai Shen
School of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine,
Wenken Liang
School of Biology and Biological Engineering, South China University of Technology
Zijian Kuang
School of Biology and Biological Engineering, South China University of Technology
Raj K. Shrestha
Flinders Health and Medical Research Institute, Flinders University, College of Medicine and Public Health
Adrienne R. Hanson
Flinders Health and Medical Research Institute, Flinders University, College of Medicine and Public Health
Scott L. Townley
Flinders Health and Medical Research Institute, Flinders University, College of Medicine and Public Health
Meiling He
School of Biology and Biological Engineering, South China University of Technology
Sishu Yu
School of Biology and Biological Engineering, South China University of Technology
Peiwen Zhou
School of Biology and Biological Engineering, South China University of Technology
Liangzhen Zhu
Department of Urology, Nanxishan Hospital of Guangxi Zhuang Autonomous Region
Zhiwen Gong
School of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine,
Xiang Ao
School of Biology and Biological Engineering, South China University of Technology
Sushma R. Rao
Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide
Qing Zhang
Kaijie Chen
School of Biology and Biological Engineering, South China University of Technology
Jinfen Wei
School of Biology and Biological Engineering, South China University of Technology
Shashikanth Marri
Flinders Health and Medical Research Institute, Flinders University, College of Medicine and Public Health
Marten F. Snel
Proteomics, Metabolomics and MS-Imaging Facility, South Australian Health and Medical Research Institute
Swati Irani
Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide
Liye Chen
School of Biology and Biological Engineering, South China University of Technology
Ling Wang
Daniel P. McDougal
Institute for Photonics and Advanced Sensing, School of Biological Sciences, The University of Adelaide
John B. Bruning
Institute for Photonics and Advanced Sensing, School of Biological Sciences, The University of Adelaide
Minglin Ou
Laboratory Center, Guangxi Key Laboratory of Metabolic Reprogramming and Intelligent Medical Engineering for Chronic Diseases, The Second Affiliated Hospital of Guilin Medical University
Shaobo Wang
Department of Basic Research, Guangzhou National Laboratory, Guangzhou International Bio-Island
Christopher G. Proud
Lifelong Health Theme, South Australian Health and Medical Research Institute
Hongli Du
School of Biology and Biological Engineering, South China University of Technology
Lisa M. Butler
Luke A. Selth
Flinders Health and Medical Research Institute, Flinders University, College of Medicine and Public Health