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

Cancer cells exhibit accelerated protein production to accommodate their high metabolic demands. This elevated protein load creates a dependency on endoplasmic reticulum-resident proteins and chaperones, which are required to maintain proteostasis. In this study, we identify 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 therapy response. PDIA1 and PDIA5 are upregulated in prostate cancer and induced by the androgen receptor (AR) signalling axis. Genetic or pharmacological targeting of PDIA1/PDIA5 causes mitochondrial dysfunction, growth inhibition and apoptosis of prostate cancer cells in vitro and in vivo. Loss of PDIA1/PDIA5 activity leads to AR ubiquitination and degradation, revealing the existence of a feedback loop between these chaperones and the AR pathway. Mechanistically, PDIA1/PDIA5 regulate AR stability by catalysing disulfide bond formation in AR, an activity that requires cysteines 670 and 845 in AR’s ligand-binding domain. Importantly, targeting PDIAs sensitizes prostate cancer cells to the AR antagonist, enzalutamide. Collectively, this study reveals a novel mechanism governing AR proteostasis in prostate cancer and positions PDIA1/5 as viable therapeutic targets.