Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama.
Center for Radioisotope and Radiopharmaceutical Technology, National Nuclear Energy Agency of Indonesia.
Biol Pharm Bull. 2021;44(11):1681-1687. doi: 10.1248/bpb.b21-00371.
The ligand-induced internalization of epidermal growth factor receptor (EGFR) is generally considered to attenuate downstream signaling via its endosomal degradation. However, the endocytosis of an oncogenic EGFR variant III (EGFRvIII) is impaired, which leads to persistent signaling from the cell surface, thereby promoting the proliferation and survival of glioblastoma multiforme (GBM) cells. Cellular stress triggers the non-canonical endocytosis-recycling of EGFR by p38-mediated phosphorylation. In the present study, we used temozolomide (TMZ), the standard chemotherapeutic agent for the treatment of GBM patients, to examine whether EGFRvIII is controlled by a non-canonical mechanism. TMZ triggered the endocytic trafficking of serine phosphorylated EGFRvIII. Moreover, phosphorylation and endocytosis were abrogated by the selective p38 inhibitor SB203580, but not gefitinib, indicating that EGFRvIII is recruited to p38-mediated non-canonical endocytosis. The combination of TMZ and SB203580 also showed potential inhibitory effects on the proliferation and motility of glioblastoma cells.
表皮生长因子受体（EGFR）的配体诱导内吞作用通常被认为通过其内体降解来减弱下游信号。然而，致癌的 EGFR 变体 III（EGFRvIII）的内吞作用受损，导致细胞表面持续信号转导，从而促进多形性胶质母细胞瘤（GBM）细胞的增殖和存活。细胞应激通过 p38 介导的磷酸化触发 EGFR 的非经典内吞-回收。在本研究中，我们使用替莫唑胺（TMZ），即治疗 GBM 患者的标准化疗药物，来检查 EGFRvIII 是否受非经典机制控制。TMZ 触发丝氨酸磷酸化 EGFRvIII 的内吞运输。此外，磷酸化和内吞作用被选择性 p38 抑制剂 SB203580 阻断，但不是吉非替尼，表明 EGFRvIII 被募集到 p38 介导的非经典内吞作用。TMZ 和 SB203580 的联合使用也对神经胶质瘤细胞的增殖和迁移表现出潜在的抑制作用。
