Selective vulnerabilities in the proteostasis network of castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) is associated with an increased reliance on heat shock protein 70 (HSP70), but it is not clear what other protein homeostasis (proteostasis) factors might be involved. To address this question, we performed functional and synthetic lethal screens in four prostate cancer cell lines. These screens confirmed key roles for HSP70, HSP90, and their co-chaperones, but also suggested that the mitochondrial chaperone, HSP60/HSPD1, is selectively required in CRPC cell lines. Knockdown of HSP60 does not impact the stability of androgen receptor (AR) or its variants; rather, it is associated with loss of mitochondrial spare respiratory capacity, partly owing to increased proton leakage. Finally, transcriptional data revealed a correlation between HSP60 levels and poor survival of prostate cancer patients. These findings suggest that re-wiring of the proteostasis network is associated with CRPC, creating selective vulnerabilities that might be targeted to treat the disease.

Cell chemical biology. 2022 Jan 27 [Epub ahead of print]

Arielle Shkedi, Isabelle R Taylor, Frank Echtenkamp, Poornima Ramkumar, Mohamed Alshalalfa, Génesis M Rivera-Márquez, Michael A Moses, Hao Shao, Robert Jeffrey Karnes, Len Neckers, Felix Feng, Martin Kampmann, Jason E Gestwicki

Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94158, USA., Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA., Department of Biochemistry and Biophysics and the Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94158, USA., Radiation Oncology, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA., Department of Urology, Mayo Clinic, Rochester, MN 55902, USA., Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: .

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