Mitochondrial unfolded protein response-dependent β-catenin signaling promotes neuroendocrine prostate cancer.

The mitochondrial unfolded protein response (UPR(mt)) maintains mitochondrial quality control and proteostasis under stress conditions. However, the role of UPR(mt) in aggressive and resistant prostate cancer is not clearly defined. We show that castration-resistant neuroendocrine prostate cancer (CRPC-NE) harbored highly dysfunctional oxidative phosphorylation (OXPHOS) Complexes. However, biochemical and protein analyses of CRPC-NE tumors showed upregulation of nuclear-encoded OXPHOS proteins and UPR(mt) in this lethal subset of prostate cancer suggestive of compensatory upregulation of stress signaling. Genetic deletion and pharmacological inhibition of the main chaperone of UPR(mt) heat shock protein 60 (HSP60) reduced neuroendocrine prostate cancer (NEPC) growth in vivo as well as reverted NEPC cells to a more epithelial-like state. HSP60-dependent aggressive NEPC phenotypes was associated with upregulation of β-catenin signaling both in cancer cells and in vivo tumors. HSP60 expression rendered enrichment of aggressive prostate cancer signatures and metastatic potential were inhibited upon suppression of UPR(mt). We discovered that UPR(mt) promoted OXPHOS functions including mitochondrial bioenergetics in CRPC-NE via regulation of β-catenin signaling. Mitochondrial biogenesis facilitated cisplatin resistance and inhibition of UPR(mt) resensitizes CRPC-NE cells to cisplatin. Together, our findings demonstrated that UPR(mt) promotes mitochondrial health via upregulating β-catenin signaling and UPR(mt) represents viable therapeutic target for NEPC.