Selective vulnerabilities in the proteostasis network of castration-resistant prostate cancer
Arielle Shkedi1, Isabelle R Taylor1, Frank Echtenkamp2
1Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94158, USA.
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.
Insights
Castration-resistant prostate cancer (CRPC) relies on heat shock proteins (HSPs). Researchers found mitochondrial HSP60 is crucial for CRPC, offering a potential new therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Castration-resistant prostate cancer (CRPC) shows increased dependence on heat shock protein 70 (HSP70).
- The role of other protein homeostasis (proteostasis) factors in CRPC remains unclear.
Purpose of the Study:
- To identify proteostasis factors selectively required in CRPC.
- To investigate the role of mitochondrial chaperones in CRPC progression.
Main Methods:
- Functional and synthetic lethal screens were conducted in four prostate cancer cell lines.
- HSP60/HSPD1 knockdown was performed to assess its impact on cellular respiration and androgen receptor (AR) stability.
- Transcriptional data analysis correlated HSP60 levels with patient survival.
Main Results:
- Screens confirmed roles for HSP70, HSP90, and co-chaperones, identifying HSP60/HSPD1 as selectively required in CRPC.
- HSP60 knockdown impaired mitochondrial respiratory capacity due to increased proton leakage, without affecting AR stability.
- Elevated HSP60 levels correlated with poorer survival in prostate cancer patients.
Conclusions:
- CRPC involves a re-wired proteostasis network, including mitochondrial chaperones like HSP60.
- Targeting HSP60 presents a potential therapeutic strategy for CRPC by exploiting its selective vulnerability.
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