Targeting ribosomal S6 kinases/Y-box binding protein-1 signaling improves cellular sensitivity to taxane in prostate cancer
Targeting ribosomal S6 kinases/Y-box binding protein-1 signaling improves cellular sensitivity to taxane in prostate cancer
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DOI：
10.1002/pros.22799
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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;Itsumi, Momoe;Naito, Seiji
研究背景紫杉烷类药物是唯一被证明能延长去势抵抗性前列腺癌患者生存期的细胞毒性化疗药物。然而，由于对紫杉烷的内在和获得性抗性，它们的治疗效率是适度的，仅带来几个月的生存益处。Y盒结合蛋白-1（YB-1）促进癌细胞对各种抗癌治疗（包括紫杉烷类）的抗性。本研究旨在阐明YB-1介导的紫杉烷类耐药机制，并通过YB-1信号转导途径研究YB-1介导的紫杉烷类耐药机制。方法采用实时荧光定量PCR和Western blot方法分别检测YB-1介导的紫杉烷类耐药基因和蛋白表达水平。我们用细胞毒性试验评估了前列腺癌细胞对紫杉烷类药物的敏感性。短叶红豆杉天然紫杉醇激活Raf-1/细胞外信号调节激酶（ERK）通路，导致核糖体S6激酶（RSK）/YB-1信号通路的激活。在前列腺癌细胞中，激活的Raf-1/ERK通路被YB-1敲低所钝化，表明Raf-1/ERK信号传导与YB-1之间的调节。此外，ERK或RSK在紫杉烷耐药前列腺癌细胞中被激活，导致YB-1激活。YB-1敲除以及RSK抑制使用RSK特异性siRNA或小分子抑制剂SL 0101成功地阻断了YB-1的激活，导致前列腺癌生长的抑制和对紫杉醇的敏感性。并暗示靶向RSK/YB-1信号传导的治疗剂如RSK抑制剂作为一种有希望的抗前列腺癌的新疗法，特别是与紫杉烷的组合。前列腺74：829-838，2014年。(c)2014 Wiley Periodicals，Inc.
BACKGROUNDTaxanes are the only cytotoxic chemotherapeutic agents proved to prolong the survival in patients with castration-resistant prostate cancer. However, because of intrinsic and acquired resistances to taxanes, their therapeutical efficiencies are modest, bringing only a few months of survival benefit. Y-box binding protein-1 (YB-1) promotes cancer cell resistance to various anticancer treatments, including taxanes. Here, we aimed to elucidate the mechanism of taxane resistance by YB-1 and examined overcoming resistance by targeting YB-1 signaling.METHODSGene and protein expression levels were evaluated by quantitative real-time polymerase chain reaction and Western blot analysis, respectively. We evaluated the sensitivity of prostate cancer cells to taxanes using cytotoxicity assays.RESULTSNatural taxane paclitaxel from Taxus brevifolia activated the Raf-1/extracellular signal-regulated kinase (ERK) pathway, leading to an activation of ribosomal S6 kinases (RSK)/YB-1 signaling. Activated Raf-1/ERK pathway was blunted by YB-1 knockdown in prostate cancer cells, indicating regulation between Raf-1/ERK signaling and YB-1. In addition, ERK or RSK was activated in taxane-resistant prostate cancer cells, resulting in YB-1 activation. YB-1 knockdown as well as RSK inhibition using RSK-specific siRNA or the small molecule inhibitor SL0101 successfully blocked activation of YB-1, leading to suppression of prostate cancer growth and sensitization to paclitaxel.CONCLUSIONSTaken together, these findings indicate that RSK/YB-1 signaling contributes to taxane resistance, and implicate the therapeutics targeting RSK/YB-1 signaling such as RSK inhibitor as a promising novel therapy against prostate cancer, especially in combination with taxane. Prostate 74:829-838, 2014. (c) 2014 Wiley Periodicals, Inc.