ArticleProceedings of the National Academy of Sciences of the United States of America2025
Protein disulfide isomerases regulate androgen receptor stability and promote prostate cancer cell growth and survival.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
What it found
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Who cites it
6 citing papers in PubMed.
- PDIA1 promotes androgen receptor activation and prostate cancer cell survival through enhancing HMMR stability.FEBS letters · 2026Article
- CDK4-selective inhibitor AU2-94 for the treatment of advanced and therapy-resistant prostate cancer.Journal of experimental & clinical cancer research : CR · 2026Article
- USP2 is an androgen-repressed survival factor that stabilises oncoproteins to facilitate therapy resistance in prostate cancer.Cell death & disease · 2026Article
- Article
- Integrative single-cell and machine-learning analysis identifies acBMC cancer · 2026Article
- Disulfidptosis and androgenic cancers: from molecular mechanisms to clinical applications and future translational research.Frontiers in endocrinology · 2026Review
Corrections and comments
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Authors and funding
30 authors.
Funding
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.
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