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

  • Cancer Sci. 2017 Sep;108(9):1820-1827. doi: 10.1111/cas.13318.
Kazuaki Kita  1 ,  Masayuki Shiota  2  3 ,  Masako Tanaka  4 ,  Asuka Otsuka  4 ,  Masaki Matsumoto  5 ,  Minoru Kato  1 ,  Satoshi Tamada  1 ,  Hiroshi Iwao  6 ,  Katsuyuki Miura  4 ,  Tatsuya Nakatani  1 ,  Shuhei Tomita  2
Affiliations
  • 1. Department of Urology, Osaka City University Medical School, Osaka, Japan.
  • 2. Department of Pharmacology, Osaka City University Medical School, Osaka, Japan.
  • 3. Department of Research Support Platform, Osaka City University Medical School, Osaka, Japan.
  • 4. Department of Applied Pharmacology and Therapeutics, Osaka City University Medical School, Osaka, Japan.
  • 5. Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
  • 6. Shitennoji University, Habikino, Japan.
PMID: 28691182 DOI: 10.1111/cas.13318
Abstract

Androgen deprivation therapy is initially effective for treating patients with advanced prostate cancer; however, the prostate Cancer gradually becomes resistant to androgen deprivation therapy, which is termed castration-resistant prostate Cancer (CRPC). Androgen Receptor splice variant 7 (AR-V7), one of the causes of CRPC, is correlated with resistance to a new-generation AR antagonist (enzalutamide) and poor prognosis. Heat shock protein 70 (HSP70) inhibitor is known to decrease the levels of full-length AR (AR-FL), but little is known about its effects against CRPC cells expressing AR-V7. In this study, we investigated the effect of the HSP70 inhibitors quercetin and VER155008 in the prostate Cancer cell line LNCaP95 that expresses AR-V7, and explored the mechanism by which HSP70 regulates AR-FL and AR-V7 expression. Quercetin and VER155008 decreased cell proliferation, increased the proportion of apoptotic cells, and decreased the protein levels of AR-FL and AR-V7. Furthermore, VER155008 decreased AR-FL and AR-V7 mRNA levels. Immunoprecipitation with HSP70 antibody and mass spectrometry identified Y-box binding protein 1 (YB-1) as one of the molecules regulating AR-FL and AR-V7 at the transcription level through interaction with HSP70. VER155008 decreased the phosphorylation of YB-1 and its localization in the nucleus, indicating that the involvement of HSP70 in AR regulation might be mediated through the activation and nuclear translocation of YB-1. Collectively, these results suggest that HSP70 inhibitors have potential anti-tumor activity against CRPC by decreasing AR-FL and AR-V7 expression through YB-1 suppression.

Keywords
Androgen receptor splice variant 7; Y-box binding protein 1; castration-resistant prostate cancer; heat shock protein 70; heat shock protein 70 inhibitor.
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