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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
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Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate

Chengfei Liu1, Wei Lou1, Joy C Yang1

  • 1Department of Urology, University of California Davis, Davis, 95817, CA, USA.

Nature Communications
|November 18, 2018
PubMed

Insights

Protein homeostasis is altered in prostate cancer resistant to advanced therapies. Inhibiting HSP70 reduces androgen receptor variant expression, overcoming drug resistance and inhibiting tumor growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Protein homeostasis (proteostasis) impacts cancer cell survival and drug resistance.
  • Androgen receptor (AR) variants drive anti-androgen resistance in advanced prostate cancer.
  • Mechanisms of AR variant regulation and proteostasis in next-generation anti-androgen resistance are unclear.

Purpose of the Study:

  • Investigate the role of proteostasis in resistance to enzalutamide/abiraterone in prostate cancer.
  • Elucidate the mechanisms regulating androgen receptor variants (AR/AR-V7).
  • Identify potential therapeutic targets to overcome anti-androgen resistance.

Main Methods:

  • Assessed ubiquitin-proteasome system (UPS) activity in resistant prostate cancer models.
  • Examined the interaction between STUB1, HSP70, and AR/AR-V7.
  • Utilized HSP70 inhibition to evaluate its effect on prostate tumor growth and AR/AR-V7 levels.
  • Correlated HSP70 and AR/AR-V7 expression in clinical prostate tumor samples.

Main Results:

  • The ubiquitin-proteasome system (UPS) is suppressed in enzalutamide/abiraterone resistant prostate cancer.
  • STUB1 and HSP70 complex interaction is crucial for AR/AR-V7 proteostasis.
  • STUB1 facilitates AR/AR-V7 ubiquitination and degradation by disassociating it from HSP70.
  • HSP70 inhibition suppressed tumor growth and enhanced treatment efficacy by reducing AR/AR-V7.
  • HSP70 is upregulated and correlates with AR/AR-V7 in high Gleason score tumors.

Conclusions:

  • Revealed a novel mechanism of anti-androgen resistance involving UPS alteration.
  • HSP70 inhibition represents a potential therapeutic strategy to overcome resistance.
  • Targeting HSP70 can reduce AR-V7 expression and improve outcomes for prostate cancer patients.

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