Temozolomide Induces Endocytosis of EGFRvIII via p38-Mediated Non-canonical Phosphorylation in Glioblastoma Cells

Ratna Dini Haryuni; Tomohiro Tanaka; Jun-ichiro Takahashi; Iimi Onuma; Yue Zhou; Satoru Yokoyama; Hiroaki Sakurai

doi:10.1248/bpb.b21-00371

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Temozolomide Induces Endocytosis of EGFRvIII via p38-Mediated Non-canonical Phosphorylation in Glioblastoma Cells

Ratna Dini Haryuni, Tomohiro Tanaka, Jun-ichiro Takahashi, Iimi Onuma, Yue Zhou, Satoru Yokoyama, Hiroaki Sakurai

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Ratna Dini Haryuni
Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama
Center for Radioisotope and Radiopharmaceutical Technology, National Nuclear Energy Agency of Indonesia
Tomohiro Tanaka
Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama
Jun-ichiro Takahashi
Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama
Iimi Onuma
Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama
Yue Zhou
Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama
Satoru Yokoyama
Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama
Hiroaki Sakurai Corresponding author
Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama

Keywords: epidermal growth factor receptor (EGFR), EGFR variant III (EGFRvIII), p38, temozolomide, endocytosis, glioblastoma

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2021 Volume 44 Issue 11 Pages 1681-1687

DOI https://doi.org/10.1248/bpb.b21-00371

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Abstract

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.

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