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Heat shock protein 70 inhibitors suppress androgen receptor expression in LNCaP95 prostate cancer cells

Kazuaki Kita1, Masayuki Shiota2,3, Masako Tanaka4

  • 1Department of Urology, Osaka City University Medical School, Osaka, Japan.

Cancer Science
|July 11, 2017
PubMed

Insights

Heat shock protein 70 (Hsp70) inhibitors like quercetin and VER155008 show promise against castration-resistant prostate cancer (CRPC) by reducing androgen receptor variants. These inhibitors target AR-V7, a key driver of CRPC, offering a potential new treatment avenue.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Advanced prostate cancer often develops resistance to androgen deprivation therapy, leading to castration-resistant prostate cancer (CRPC).
  • Androgen receptor splice variant 7 (AR-V7) is a significant factor in CRPC development and is associated with resistance to treatments like enzalutamide.
  • The role of heat shock protein 70 (Hsp70) inhibitors in targeting AR-V7-expressing CRPC cells remains largely unexplored, despite their known effects on full-length androgen receptor (AR-FL).

Purpose of the Study:

  • To investigate the anti-tumor effects of Hsp70 inhibitors, quercetin and VER155008, on CRPC cells expressing AR-V7.
  • To elucidate the mechanism by which Hsp70 regulates the expression of AR-FL and AR-V7 in prostate cancer.

Main Methods:

  • Utilized the LNCaP95 prostate cancer cell line, which expresses AR-V7.
  • Administered Hsp70 inhibitors quercetin and VER155008 to cell cultures.
  • Assessed cell proliferation, apoptosis, and protein/mRNA levels of AR-FL and AR-V7.
  • Employed immunoprecipitation and mass spectrometry to identify interacting proteins with Hsp70.
  • Analyzed Y-box binding protein 1 (YB-1) phosphorylation and nuclear localization.

Main Results:

  • Both quercetin and VER155008 significantly reduced cell proliferation and increased apoptosis in AR-V7-expressing CRPC cells.
  • Hsp70 inhibitors decreased the protein levels of both AR-FL and AR-V7.
  • VER155008 also reduced the mRNA levels of AR-FL and AR-V7.
  • Y-box binding protein 1 (YB-1) was identified as a key regulator interacting with Hsp70.
  • VER155008 treatment led to decreased YB-1 phosphorylation and nuclear translocation, suggesting Hsp70's role in AR regulation via YB-1.

Conclusions:

  • Hsp70 inhibitors demonstrate significant anti-tumor activity against CRPC cells expressing AR-V7.
  • These inhibitors effectively decrease both AR-FL and AR-V7 expression.
  • The mechanism involves the suppression of YB-1 activation and nuclear import, mediated by Hsp70 inhibition.
Keywords:
Androgen receptor splice variant 7Y-box binding protein 1castration-resistant prostate cancerheat shock protein 70heat shock protein 70 inhibitor

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