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

Oncogene volume 44, pages 820–834 (2025)Cite this article

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Abstract

The mitochondrial unfolded protein response (UPRmt) maintains mitochondrial quality control and proteostasis under stress conditions. However, the role of UPRmt 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 UPRmt in this lethal subset of prostate cancer suggestive of compensatory upregulation of stress signaling. Genetic deletion and pharmacological inhibition of the main chaperone of UPRmt 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 UPRmt. We discovered that UPRmt promoted OXPHOS functions including mitochondrial bioenergetics in CRPC-NE via regulation of β-catenin signaling. Mitochondrial biogenesis facilitated cisplatin resistance and inhibition of UPRmt resensitizes CRPC-NE cells to cisplatin. Together, our findings demonstrated that UPRmt promotes mitochondrial health via upregulating β-catenin signaling and UPRmt represents viable therapeutic target for NEPC.

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Fig. 1: Mitochondria are dysfunctional in neuroendocrine prostate tumors.
Fig. 2: HSP60 expression is upregulated in NEPC.
Fig. 3: HSP60 regulates NEPC markers.
Fig. 4: Loss of HSP60 in NEPC reduces oncogenic burden in vivo.
Fig. 5: HSP60 mRNA expression correlates with enrichment in gene sets involving mitochondrial function and aggressive phenotypes.
Fig. 6: HSP60 inhibition reduces migration and invasion in CRPC cells.
Fig. 7: HSP60 and β-catenin alter mitochondrial bioenergetics.
Fig. 8: HSP60 inhibition sensitizes aggressive prostate cancer cells to cisplatin.

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All data associated with this study are present in the paper and/or the Supplementary informations.

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Funding

This work was supported by the NCI of the NIH under Award Number R01-CA160685 and R01CA246437 (to D. Chandra), the American Cancer Society under award number MBG-21-048-01-MBG and RSG-12-214-01 – CCG (to D. Chandra), Roswell Park Alliance Foundation (to DC), and in part by the NCI Center Support Grant P30-CA016056 to the Roswell Park Comprehensive Cancer Center that supports the Translational Imaging, Pathology Network, Flow and Image Cytometry, Bioinformatics, Biostatistics, Genomic, Animal housing facility Shared Resources and the Onsite Supply Center. We thank Drs. David Goodrich, Dean G Tang, Barbara Foster, and Raghu Gogada for their technical support and reagents.

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Authors and Affiliations

  1. Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA

    Jordan Alyse Woytash, Rahul Kumar, Ajay K. Chaudhary, Cullan Donnelly, Adam Wojtulski, Murali Bethu, Neelu Yadav, Joseph R. Inigo & Dhyan Chandra

  2. Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA

    Jianmin Wang

  3. Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA

    Joseph Spernyak

  4. Research Unit for Molecular Medicine, Aarhus University and Aarhus University Hospital, 8200, Aarhus N, Denmark

    Peter Bross

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  1. Jordan Alyse Woytash
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Contributions

DC, JAW, and RK designed experiments. JAW, RK, AKC, CD, AW, NY, MB, JRI, and JW performed experiments. JS helped with analysis of MR imaging and PB provided HSPD1 mouse. JAW performed statistical and bioinformatic analysis. DC, JAW, and RK analyzed the data. DC and JAW wrote the paper. DC conceived the idea and supervised the study.

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Correspondence to Dhyan Chandra.

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The authors confirm that all methods were performed in accordance with the relevant guidelines and regulations. For all mouse experiments (including all GEMM and tumor xenograft experiments), approval has been obtained from the Institutional Animal Care and Use Committee at Roswell Park Comprehensive Cancer Center (IACUC Approval # 1306 M). This work does not involve human research.

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Woytash, J.A., Kumar, R., Chaudhary, A.K. et al. Mitochondrial unfolded protein response-dependent β-catenin signaling promotes neuroendocrine prostate cancer. Oncogene 44, 820–834 (2025). https://doi.org/10.1038/s41388-024-03261-4

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