Gefitinib induces EGFR and α5β1 integrin co-endocytosis in glioblastoma cells
Gefitinib induces EGFR and α5β1 integrin co-endocytosis in glioblastoma cells
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DOI：
10.1007/s00018-020-03686-6
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发表时间：
2020-11-05
影响因子：
8
通讯作者：
Lehmann, Maxime
中科院分区：
文献类型：
--
作者：
Blandin, Anne-Florence;Da Silva, Elisabete Cruz;Lehmann, Maxime
EGFR的过表达促进了胶质母细胞瘤(GBM)细胞的侵袭，但这些肿瘤仍然对EGFR靶向治疗如酪氨酸激酶抑制剂(TKIs)具有耐药性。内吞作用是EGFR功能的重要调节因子，在胶质瘤细胞中常处于失调状态，并与治疗耐药有关。然而，在GBM细胞中，TKI对EGFR内吞作用的影响从未被研究过。在目前的研究中，我们证明了吉非替尼和其他酪氨酸激酶抑制剂通过增加内吞作用在早期内吞体内诱导了EGFR积聚。此外，TKI还触发了另一种膜受体--纤维连接蛋白受体α5beta1整合素的早期内吞定位，这是GBM中一个有希望的治疗靶点，调节癌细胞中生理性的EGFR内吞和循环。超分辨dSTORM成像显示，在吉非替尼处理的细胞内膜隔室中，β1整合素和EGFR之间有很近的距离，这表明它们之间可能存在相互作用。有趣的是，整合素缺失延迟了吉非替尼介导的EGFR内吞作用。EGFR和α5β1整合素的共同内吞可能改变胶质瘤细胞对吉非替尼的反应。使用球形胶质瘤细胞扩散的体外模型，我们发现Alpha5整合素缺失的细胞比Alpha5表达的细胞对TKI更敏感。这项工作首次提供了证据，证明EGFR TKI可以触发大量的EGFR和α5β1整合素共内吞，这可能在治疗治疗中调节胶质瘤细胞的侵袭性。
Overexpression of EGFR drives glioblastomas (GBM) cell invasion but these tumours remain resistant to EGFR-targeted therapies such as tyrosine kinase inhibitors (TKIs). Endocytosis, an important modulator of EGFR function, is often dysregulated in glioma cells and is associated with therapy resistance. However, the impact of TKIs on EGFR endocytosis has never been examined in GBM cells. In the present study, we showed that gefitinib and other tyrosine kinase inhibitors induced EGFR accumulation in early-endosomes as a result of an increased endocytosis. Moreover, TKIs trigger early-endosome re-localization of another membrane receptor, the fibronectin receptor alpha5beta1 integrin, a promising therapeutic target in GBM that regulates physiological EGFR endocytosis and recycling in cancer cells. Super-resolution dSTORM imaging showed a close-proximity between beta1 integrin and EGFR in intracellular membrane compartments of gefitinib-treated cells, suggesting their potential interaction. Interestingly, integrin depletion delayed gefitinib-mediated EGFR endocytosis. Co-endocytosis of EGFR and alpha5beta1 integrin may alter glioma cell response to gefitinib. Using an in vitro model of glioma cell dissemination from spheroid, we showed that alpha5 integrin-depleted cells were more sensitive to TKIs than alpha5-expressing cells. This work provides evidence for the first time that EGFR TKIs can trigger massive EGFR and alpha5beta1 integrin co-endocytosis, which may modulate glioma cell invasiveness under therapeutic treatment.