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

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.

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

MeSH terms

  • Anisomycin / pharmacology
  • Antineoplastic Agents / pharmacology*
  • Blotting, Western
  • Cell Line, Tumor
  • Electrophoresis, Polyacrylamide Gel
  • Endocytosis / drug effects*
  • ErbB Receptors / metabolism*
  • Fluorescent Antibody Technique
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Humans
  • Phosphorylation / drug effects
  • Temozolomide / pharmacology*
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Antineoplastic Agents
  • epidermal growth factor receptor VIII
  • Anisomycin
  • ErbB Receptors
  • p38 Mitogen-Activated Protein Kinases
  • Temozolomide