DDX17 nucleocytoplasmic shuttling promotes acquired gefitinib resistance in non-small cell lung cancer cells via activation of β-catenin
DDX17 nucleocytoplasmic shuttling promotes acquired gefitinib resistance in non-small cell lung cancer cells via activation of β-catenin
复制标题
DDX17 核质穿梭通过激活 β-catenin 促进非小细胞肺癌细胞获得吉非替尼耐药。
DOI：
10.1016/j.canlet.2017.02.029
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发表时间：
2017-08-01
期刊：
影响因子：
9.7
通讯作者：
Wei, Yuquan
中科院分区：
文献类型：
--
作者：
Li, Kai;Mo, Chunfen;Wei, Yuquan
尽管表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）对EGFR突变的非小细胞肺癌（NSCLC）患者有效，但几乎所有这些患者最终都会对EGFR-TKI产生获得性耐药。然而，导致吉非替尼耐药性的分子机制仍然没有完全了解。在这里，我们报告说，DDX 17水平升高，观察到吉非替尼耐药的NSCLC细胞比吉非替尼敏感的细胞。DDX 17的上调增强吉非替尼抗性，而DDX 17沉默的细胞部分恢复吉非替尼敏感性。从机制上讲，我们证明了DDX 17使E-钙粘蛋白/β-连环蛋白复合物解离，导致β-连环蛋白核转位，随后增加β-连环蛋白靶基因的转录。此外，我们确定了两个核定位信号（NLS）和四个核输出信号（内斯）序列介导的DDX 17核质穿梭通过输出/输入依赖的途径。DDX 17的动态核质穿梭的中断损害了DDX 17介导的β-连环蛋白的活化和NSCLC细胞中的获得性耐药性。总之，我们的研究结果揭示了一种新的和重要的机制，DDX 17通过输出蛋白/输入蛋白依赖性细胞质穿梭和随后的β-连环蛋白激活而导致吉非替尼获得性耐药，DDX 17抑制可能是克服NSCLC患者吉非替尼获得性耐药的一种有前途的策略。(C)2017爱思唯尔B. V.保留所有权利。
Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective for non-small cell lung cancer (NSCLC) patients with EGFR mutations, almost all these patients will eventually develop acquired resistance to EGFR-TKI. However, the molecular mechanisms responsible for gefitinib resistance remain still not fully understood. Here, we report that elevated DDX17 levels are observed in gefitinib-resistant NSCLC cells than gefitinib-sensitive cells. Upregulation of DDX17 enhances the gefitinib resistance, whereas DDX17-silenced cells partially restore gefitinib sensitivity. Mechanistically, we demonstrate that DDX17 disassociates the E-cadherin/beta-catenin complex, resulting in beta-catenin nuclear translocation and subsequently augmenting the transcription of beta-catenin target genes. Moreover, we identify two nuclear localization signal (NLS) and four nuclear export signal (NES) sequences mediated DDX17 nucleocytoplasmic shuttling via an exportin/importin-dependent pathways. Interruption of dynamic nucleocytoplasmic shuttling of DDX17 impairs DDX17-mediating the activation of beta-catenin and acquired resistance in NSCLC cells. In conclusion, our findings reveal a novel and important mechanism by which DDX17 contributes to acquired gefitinib resistance through exportin/importin-dependent cytoplasmic shuttling and followed by activation of beta-catenin, and DDX17 inhibition may be a promising strategy to overcome acquired resistance of gefitinib in NSCLC patients. (C) 2017 Elsevier B.V. All rights reserved.