Protein disulfide isomerases regulate androgen receptor stability and promote prostate cancer cell growth and survival

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.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-10-14
DOI
https://doi.org/10.1073/pnas.2509222122
Citations
3
Primary Topic
Endoplasmic Reticulum Stress and Disease
Type
article
Field-Weighted Citation Impact
3.45
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article

Protein disulfide isomerases regulate androgen receptor stability and promote prostate cancer cell growth and survival

Daniel P. McDougal, Adrienne R. Hanson, Wenken Liang, Luke A. Selth et al.
3 citations
Proceedings of the National Academy of Sciences
Endoplasmic Reticulum Stress and Disease
3.45
article

Protein disulfide isomerases regulate androgen receptor stability and promote prostate cancer cell growth and survival

Daniel P. McDougal, Adrienne R. Hanson, Wenken Liang, Luke A. Selth, Scott L. Townley, Peiwen Zhou, Swati Irani, Chen Kai-jie, Xiang Ao, Christopher G. Proud, Shashikanth Marri, Lisa M. Butler, Liye Chen, Meiling He, John B. Bruning, Sushma R. Rao, Jianling Xie, Lijuan Zhu, Minglin Ou, Zhiwen Gong, Marten F. Snel, Qing Zhang, Ling Wang, Hongli Du, Shaobo Wang, Raj K. Shrestha, Kaikai Shen, Sixian Yu, Jinfen Wei, Z X Kuang
article en
3 citations

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.

Proceedings of the National Academy of SciencesVol. 122(42)
The University of Melbourne (AU), Flinders University (AU), Guilin Medical University (CN), Australian Institute of Business (AU), Flinders Medical Centre (AU), Guangzhou Experimental Station (CN), First Affiliated Hospital of Guangzhou Medical University (CN), Shanghai University of Traditional Chinese Medicine (CN), Guangzhou Regenerative Medicine and Health Guangdong Laboratory (CN), Adelaide Institute for Sleep Health (AU), South Australian Health and Medical Research Institute (AU), Centre for Cancer Biology (AU), Nanxi Mountain Hospital (CN), Freemasons Foundation Centre for Men's Health (AU), The University of Adelaide (AU), Hainan Medical University (CN), South China University of Technology (CN), Guangzhou Medical University (CN)
Openalex Percentile: Top 7%
Endoplasmic Reticulum Stress and Disease
3.45
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