Open AccessHeat shock protein 70 inhibitors suppress androgen receptor expression in LNC aP95 prostate cancer cells
Author(s) -
Kita Kazuaki,
Shiota Masayuki,
Tanaka Masako,
Otsuka Asuka,
Matsumoto Masaki,
Kato Minoru,
Tamada Satoshi,
Iwao Hiroshi,
Miura Katsuyuki,
Nakatani Tatsuya,
Tomita Shuhei
Publication year - 2017
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13318
Subject(s) - prostate cancer , androgen receptor , hsp70 , cancer research , androgen deprivation therapy , enzalutamide , immunoprecipitation , heat shock protein , androgen , chemistry , endocrinology , medicine , biology , cancer , antibody , immunology , biochemistry , hormone , gene
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 VER 155008 in the prostate cancer cell line LNC aP95 that expresses AR ‐V7, and explored the mechanism by which Hsp70 regulates AR ‐ FL and AR ‐V7 expression. Quercetin and VER 155008 decreased cell proliferation, increased the proportion of apoptotic cells, and decreased the protein levels of AR ‐ FL and AR ‐V7. Furthermore, VER 155008 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. VER 155008 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.