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首页> 外文期刊>Neoplasia: an international journal for oncology research >Ezrin Enhances EGFR Signaling and Modulates Erlotinib Sensitivity in Non–Small Cell Lung Cancer Cells
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Ezrin Enhances EGFR Signaling and Modulates Erlotinib Sensitivity in Non–Small Cell Lung Cancer Cells

机译：Ezrin增强EGFR信号传导，并调节非小细胞肺癌细胞中的orlotinib敏感性

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Ezrin is a scaffolding protein that is involved in oncogenesis by linking cytoskeletal and membrane proteins. Ezrin interacts with epidermal growth factor receptor (EGFR) in the cell membrane, but little is known about the effects of this interaction on EGFR signaling pathway. In this study, we established the biological and functional significance of ezrin-EGFR interaction in non–small cell lung cancer (NSCLC) cells. Endogenous ezrin and EGRF interaction was confirmed by co-immunoprecipitation and immunofluorescent staining. When expression of ezrin was inhibited, EGFR activity and phosphorylation levels of downstream signaling pathway proteins ERK and STAT3 were decreased. Cell fractionation experiments revealed that nuclear EGFR was significantly diminished in ezrin-knockdown cells. Consequently, mRNA levels of EGFR target genes AURKA, COX-2, cyclin D1, and iNOS were decreased in ezrin-depleted cells. A small molecule inhibitor of ezrin, NSC305787, reduced EGF-induced phosphorylation of EGFR and downstream target proteins, EGFR nuclear translocation, and mRNA levels of nuclear EGFR target genes similar to ezrin suppression. NSC305787 showed synergism with erlotinib in wild-type EGFR-expressing NSCLC cells, whereas no synergy was observed in EGFR-null cells. Phosphorylation of ezrin on Y146 was found as an enhancer of ezrin-EGFR interaction and required for increased proliferation, colony formation, and drug resistance to erlotinib. These findings suggest that ezrin-EGFR interaction augments oncogenic functions of EGFR and that targeting ezrin may provide a potential novel approach to overcome erlotinib resistance in NSCLC cells.
机译：Ezrin是一种脚手架蛋白，其通过连接细胞骨骼和膜蛋白而参与血管生成。 Ezrin在细胞膜中与表皮生长因子受体（EGFR）相互作用，但关于该相互作用对EGFR信号传导途径的影响很少。在这项研究中，我们建立了非小细胞肺癌（NSCLC）细胞中Ezrin-Egfr相互作用的生物学和功能意义。通过共免疫沉淀和免疫荧光染色证实了内源性Ezrin和EGRF相互作用。当抑制EZRIN的表达时，降低了下游信号通路蛋白ERK和STAT3的EGFR活性和磷酸化水平。细胞分级实验表明，在Ezrin敲低细胞中核EGFR显着降低。因此，在Ezrin耗尽的细胞中降低了EGFR靶基因Aurka，Cox-2，细胞周期蛋白D1和InOS的MRNA水平。 Ezrin，NSC305787的小分子抑制剂，降低EGF诱导的EGFR和下游靶蛋白的磷酸化，EGFR核易位和类似于Ezrin抑制的核EGFR靶基因的mRNA水平。 NSC305787在野生型EGFR表达的NMSCLC细胞中显示出与厄洛替尼的协同作用，而在EGFR-NULL细胞中没有观察到协同作用。发现EZRIN对Y146的磷酸化作为Ezrin-EGFR相互作用的增强剂，并且增加增殖，菌落形成和对厄洛替尼的耐药性。这些发现表明，Ezrin-EGFR相互作用增强EGFR的致癌功能，靶向EZRIN可以提供克服NSCLC细胞中欧洛替尼抗性的潜在新方法。

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