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

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.

• Authors: Kazuaki Kita, Masayuki Shiota, Masako Tanaka, Asuka Otsuka, Masaki Matsumoto, Minoru Kato, Satoshi Tamada, Hiroshi Iwao, Katsuyuki Miura, Tatsuya Nakatani, Shuhei Tomita
• Journal: Cancer science (Cancer Sci) Vol. 108 Issue 9 Pg. 1820-1827 (Sep 2017) ISSN: 1349-7006 [Electronic] England
• PMID: 28691182 (Publication Type: Journal Article)
• Copyright: © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Antineoplastic Agents, Hormonal
• HSP70 Heat-Shock Proteins
• Purine Nucleosides
• Receptors, Androgen
• VER 155008
• Y-Box-Binding Protein 1
• YBX1 protein, human
• Quercetin

Topics

• Antineoplastic Agents, Hormonal (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Gene Expression (drug effects)
• Gene Silencing (drug effects)
• HSP70 Heat-Shock Proteins (antagonists & inhibitors, metabolism)
• Humans
• Male
• Prostatic Neoplasms (drug therapy, metabolism)
• Purine Nucleosides (pharmacology)
• Quercetin (pharmacology)
• Receptors, Androgen (genetics, metabolism)
• Y-Box-Binding Protein 1 (metabolism)