Targeting mitochondrial unfolded protein response to develop novel cancer therapeutics
The mitochondrial unfolded protein response (UPRmt) is crucial for maintenance of mitochondrial protein homeostasis (proteostasis), cellular functions, and survival.
We identified that the two key components of the UPRmt, heat shock protein 60 (HSP60, a mitochondrial chaperonin) and caseinolytic protease (ClpP, a mitochondrial protease), are required for the development of advanced prostate cancer.
HSP60 maintains bioenergetic function (ATP producing function) of mitochondria via interacting with ClpP. We identified a novel UPRmt inhibitor that blocks HSP60 interaction with ClpP and abrogates survival signaling.
Our goal is to develop UPRmt-based novel therapeutics for prostate and other types of aggressive cancer.
- Kumar R, et al. A mitochondrial unfolded protein response inhibitor suppresses prostate cancer growth in mice via HSP60. J Clin Invest. 2022 Jul 1;132(13):e149906. doi: 10.1172/JCI149906. PMID: 35653190; PMCID: PMC9246382.
- Inigo JR, Chandra D. The mitochondrial unfolded protein response (UPRmt): shielding against toxicity to mitochondria in cancer. J Hematol Oncol. 2022 Jul 21;15(1):98. doi: 10.1186/s13045-022-01317-0. PMID: 35864539; PMCID: PMC9306209.
- Inigo JR, et al. Targeting the mitochondrial unfolded protein response in cancer: opportunities and challenges. Trends Cancer. 2021 Dec;7(12):1050-1053. doi: 10.1016/j.trecan.2021.08.008. Epub 2021 Sep 24. PMID: 34580036; PMCID: PMC9287746.
- O'Malley J, et al. Mitochondrial Stress Response and Cancer. Trends Cancer. 2020 Aug;6(8):688-701. doi: 10.1016/j.trecan.2020.04.009. Epub 2020 May 22. PMID: 32451306; PMCID: PMC7392807.
Connect with the Chandra Lab
Department of Pharmacology & Therapeutics
Roswell Park Comprehensive Cancer Center
Elm and Carlton Streets
Buffalo, NY 14263