Ezrin Enhances EGFR Signaling and Modulates Erlotinib Sensitivity in Non-Small Cell Lung Cancer Cells.
Ezrin Enhances EGFR Signaling and Modulates Erlotinib Sensitivity in Non-Small Cell Lung Cancer Cells.
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DOI：
10.1016/j.neo.2016.01.002
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发表时间：
2016-02
期刊：
影响因子：
4.8
通讯作者：
Uren, Aykut
中科院分区：
文献类型：
--
作者：
Saygideger-Kont, Yasemin;Minas, Tsion Zewdu;Jones, Hayden;Hour, Sarah;Celik, Haydar;Temel, Idil;Han, Jenny;Atabey, Nese;Erkizan, Hayriye Verda;Toretsky, Jeffrey A.;Uren, Aykut
Ezrin是一种支架蛋白，通过连接细胞骨架蛋白和膜蛋白参与肿瘤的发生。Ezrin与细胞膜上的表皮生长因子受体（EGFR）相互作用，但对这种相互作用对EGFR信号通路的影响知之甚少。在本研究中，我们确定了ezrin-EGFR相互作用在非小细胞肺癌（NSCLC）细胞中的生物学和功能意义。通过免疫共沉淀和免疫荧光染色证实内源性ezrin与EGRF相互作用。当ezrin的表达受到抑制时，EGFR活性和下游信号通路蛋白ERK和STAT3的磷酸化水平降低。细胞分离实验显示，在ezrin敲除的细胞中，细胞核EGFR显著减少。因此，EGFR靶基因AURKA、COX-2、cyclin D1和iNOS的mRNA水平在ezrin缺失的细胞中降低。作为ezrin的一种小分子抑制剂，NSC305787可以降低egf诱导的EGFR和下游靶蛋白的磷酸化、EGFR核易位以及核EGFR靶基因的mRNA水平，类似于ezrin的抑制。NSC305787在野生型表达egfr的NSCLC细胞中显示出与厄洛替尼的协同作用，而在egfr无效的细胞中没有观察到协同作用。Y146上ezrin的磷酸化被发现是ezrin- egfr相互作用的增强剂，并且是增加增殖、集落形成和对厄洛替尼耐药所必需的。这些发现表明ezrin-EGFR相互作用增强了EGFR的致癌功能，并且靶向ezrin可能为克服NSCLC细胞中厄洛替尼耐药提供了一种潜在的新方法。
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.
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