A mitochondrial unfolded protein response inhibitor suppresses prostate cancer growth in mice via HSP60

Mitochondrial proteostasis, regulated by the mitochondrial unfolded protein response (UPR(mt)), is crucial for maintenance of cellular functions and survival. Elevated oxidative and proteotoxic stress in mitochondria must be attenuated by the activation of a ubiquitous UPR(mt) to promote prostate cancer (PCa) growth. Here we show that the 2 key components of the UPR(mt), heat shock protein 60 (HSP60, a mitochondrial chaperonin) and caseinolytic protease P (ClpP, a mitochondrial protease), were required for the development of advanced PCa. HSP60 regulated ClpP expression via c-Myc and physically interacted with ClpP to restore mitochondrial functions that promote cancer cell survival. HSP60 maintained the ATP-producing functions of mitochondria, which activated the β-catenin pathway and led to the upregulation of c-Myc. We identified a UPR(mt) inhibitor that blocked HSP60’s interaction with ClpP and abrogated survival signaling without altering HSP60’s chaperonin function. Disruption of HSP60-ClpP interaction with the UPR(mt) inhibitor triggered metabolic stress and impeded PCa-promoting signaling. Treatment with the UPR(mt) inhibitor or genetic ablation of Hsp60 inhibited PCa growth and progression. Together, our findings demonstrate that the HSP60-ClpP–mediated UPR(mt) is essential for prostate tumorigenesis and the HSP60-ClpP interaction represents a therapeutic vulnerability in PCa.