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.