1. Selective vulnerabilities in the proteostasis network of castration-resistant prostate cancer.
- Author
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Shkedi A, Taylor IR, Echtenkamp F, Ramkumar P, Alshalalfa M, Rivera-Márquez GM, Moses MA, Shao H, Karnes RJ, Neckers L, Feng F, Kampmann M, and Gestwicki JE
- Subjects
- Cell Line, Tumor, HSP70 Heat-Shock Proteins metabolism, HSP90 Heat-Shock Proteins genetics, HSP90 Heat-Shock Proteins metabolism, Humans, Male, Molecular Chaperones metabolism, Proteostasis, Receptors, Androgen genetics, Receptors, Androgen metabolism, Prostatic Neoplasms, Castration-Resistant genetics
- Abstract
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., Competing Interests: Declaration of interests J.E.G. holds patents to the use of HSP70 inhibitors and is a member of the Cell Chemical Biology Scientific Advisory Board. The authors declare no other competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
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