TY - JOUR
T1 - Heat shock protein 70 inhibitors suppress androgen receptor expression in LNCaP95 prostate cancer cells
AU - Kita, Kazuaki
AU - Shiota, Masayuki
AU - Tanaka, Masako
AU - Otsuka, Asuka
AU - Matsumoto, Masaki
AU - Kato, Minoru
AU - Tamada, Satoshi
AU - Iwao, Hiroshi
AU - Miura, Katsuyuki
AU - Nakatani, Tatsuya
AU - Tomita, Shuhei
N1 - Funding Information:
The authors wish to thank members of the Central Laboratory of Osaka City University Graduate School of Medicine for technical support. This work was partly undertaken in the Cooperative Research Project Program of the Medical Institute of Bioregulation, Kyushu University.
Publisher Copyright:
© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
PY - 2017/9
Y1 - 2017/9
N2 - 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.
AB - 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.
KW - Androgen receptor splice variant 7
KW - Y-box binding protein 1
KW - castration-resistant prostate cancer
KW - heat shock protein 70
KW - heat shock protein 70 inhibitor
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U2 - 10.1111/cas.13318
DO - 10.1111/cas.13318
M3 - Article
C2 - 28691182
AN - SCOPUS:85028604325
SN - 1347-9032
VL - 108
SP - 1820
EP - 1827
JO - Cancer Science
JF - Cancer Science
IS - 9
ER -