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Inhibition of RSK/YB‐1 signaling enhances the anti‐cancer effect of enzalutamide in prostate cancer
Author(s) -
Shiota Masaki,
Yokomizo Akira,
Takeuchi Ario,
Itsumi Momoe,
Imada Kenjiro,
Kashiwagi Eiji,
Inokuchi Junichi,
Tatsugami Katsunori,
Uchiumi Takeshi,
Naito Seiji
Publication year - 2014
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.22813
Subject(s) - enzalutamide , prostate cancer , androgen receptor , cancer research , lncap , phosphorylation , signal transduction , androgen deprivation therapy , medicine , androgen , kinase , cancer , endocrinology , biology , microbiology and biotechnology , hormone
BACKGROUND Previously, we have shown that Y‐box binding protein‐1 (YB‐1) regulates androgen receptor (AR) expression and contributes to castration resistance. However, the mechanism of YB‐1 activation remains unknown. In this study, we aimed to elucidate the mechanism and role of YB‐1 activation in relation to castration resistance as well as enzalutamide resistance, with a view to developing a novel therapeutic concept for castration‐resistant prostate cancer (CRPC) treatment. METHODS The expression and phosphorylation levels of ribosomal S6 kinase 1 (RSK1), YB‐1 and AR were examined by quantitative PCR and Western blotting using prostate cancer cells. In addition, the effects of YB‐1 inhibition using specific siRNA and small molecule inhibitor SL0101 on AR expression as well as combination treatment with enzalutamide and SL0101 were examined. RESULTS We found that androgen deprivation, as well as treatment with the next‐generation anti‐androgen enzalutamide, induced RSK1 and YB‐1 activation followed by AR induction, which could be reversed by YB‐1 shutdown and RSK inhibitor SL0101. SL0101 and enzalutamide exerted a synergistic tumor‐suppressive effect on cell proliferation in androgen‐dependent prostate cancer LNCaP cells, as well as castration‐resistant C4‐2 cells. Furthermore, the phosphorylation levels of RSK1 and YB‐1 were elevated in castration‐ and enzalutamide‐resistant cells, compared with their parental cells. CONCLUSIONS Taken together, these findings indicate that RSK1/YB‐1 signaling contributes to castration as well as enzalutamide resistance, and that the therapeutic targeting of RSK1/YB‐1 signaling would be a promising novel therapy against prostate cancer, especially CRPC when combined with enzalutamide. Prostate 74:959–969, 2014 . © 2014 Wiley Periodicals, Inc.