Inhibition of RSK/YB-1 Signaling Enhances the Anti-Cancer Effect of Enzalutamide in Prostate Cancer
Inhibition of RSK/YB-1 Signaling Enhances the Anti-Cancer Effect of Enzalutamide in Prostate Cancer
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DOI：
10.1002/pros.22813
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发表时间：
2014-06-01
期刊：
影响因子：
2.8
通讯作者：
Naito, Seiji
中科院分区：
文献类型：
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作者：
Shiota, Masaki;Yokomizo, Akira;Naito, Seiji
背景以前，我们已经证明Y盒结合蛋白-1（YB-1）调节雄激素受体（AR）的表达，并有助于去势抵抗。然而，YB-1激活的机制仍然未知。在这项研究中，我们的目的是阐明YB-1激活与去势抵抗以及恩杂鲁胺抵抗相关的机制和作用，以期为去势抵抗性前列腺癌（CRPC）的治疗开发一种新的治疗概念。用定量PCR和Western blotting检测前列腺癌细胞YB-1和AR。此外，检测了使用特异性siRNA和小分子抑制剂SL 0101抑制YB-1对AR表达的作用以及用恩杂鲁胺和SL 0101的组合治疗。我们发现雄激素剥夺以及用下一代抗雄激素恩杂鲁胺的治疗诱导RSK 1和YB-1活化，随后是AR诱导。YB-1停堆和RSK抑制剂SL 0101可逆转这一趋势。SL 0101和恩杂鲁胺对雄激素依赖性前列腺癌LNCaP细胞以及去势抵抗性C4-2细胞的细胞增殖具有协同肿瘤抑制作用。此外，RSK 1和YB-1的磷酸化水平在去势和恩杂鲁胺耐药细胞中升高，与它们的亲本cells. CONCLUSION综合起来，这些发现表明RSK 1/YB-1信号传导有助于去势以及恩杂鲁胺耐药，并且RSK 1/YB-1信号传导的治疗靶向将是一种有希望的针对前列腺癌的新疗法。尤其是CRPC与恩杂鲁胺联用时。前列腺74：959-969，2014年。(c)2014 Wiley Periodicals，Inc.
BACKGROUNDPreviously, 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.METHODSThe 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.RESULTSWe 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.CONCLUSIONSTaken 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. (c) 2014 Wiley Periodicals, Inc.