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

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

doi:10.1016/j.chembiol.2022.01.008

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

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

Urology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	490-501.e4
Journal	Cell Chemical Biology
Volume	29
Issue number	3
DOIs	https://doi.org/10.1016/j.chembiol.2022.01.008
State	Published - Mar 17 2022

Keywords

chaperones
functional genomics
heat shock proteins
mitochondria
prostate cancer
proteostasis
shRNA

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

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10.1016/j.chembiol.2022.01.008

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Shkedi, A., Taylor, I. R., Echtenkamp, F., Ramkumar, P., Alshalalfa, M., Rivera-Márquez, G. M., Moses, M. A., Shao, H., Karnes, R. J., Neckers, L., Feng, F., Kampmann, M., & Gestwicki, J. E. (2022). Selective vulnerabilities in the proteostasis network of castration-resistant prostate cancer. Cell Chemical Biology, 29(3), 490-501.e4. https://doi.org/10.1016/j.chembiol.2022.01.008

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 & Gestwicki, JE 2022, 'Selective vulnerabilities in the proteostasis network of castration-resistant prostate cancer', Cell Chemical Biology, vol. 29, no. 3, pp. 490-501.e4. https://doi.org/10.1016/j.chembiol.2022.01.008

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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.",

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AU - Karnes, Robert Jeffrey

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AU - Kampmann, Martin

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AB - 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.

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

Abstract

Keywords

ASJC Scopus subject areas

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