Role of Endocytosis Proteins in Gefitinib-Mediated EGFR Internalisation in Glioma Cells.
Fiche publication
Date publication
novembre 2021
Journal
Cells
Auteurs
Membres identifiés du Cancéropôle Est :
Dr CHOULIER Laurence, Pr DEDIEU Stéphane, Pr LEHMANN Maxime, Dr RONDE Philippe, Dr THEVENARD-DEVY Jessica, Dr SCHNEIDER Christophe
Tous les auteurs :
Cruz Da Silva E, Choulier L, Thevenard-Devy J, Schneider C, Carl P, Rondé P, Dedieu S, Lehmann M
Lien Pubmed
Résumé
EGFR (epidermal growth factor receptor), a member of the ErbB tyrosine kinase receptor family, is a clinical therapeutic target in numerous solid tumours. EGFR overexpression in glioblastoma (GBM) drives cell invasion and tumour progression. However, clinical trials were disappointing, and a molecular basis to explain these poor results is still missing. EGFR endocytosis and membrane trafficking, which tightly regulate EGFR oncosignaling, are often dysregulated in glioma. In a previous work, we showed that EGFR tyrosine kinase inhibitors, such as gefitinib, lead to enhanced EGFR endocytosis into fused early endosomes. Here, using pharmacological inhibitors, siRNA-mediated silencing, or expression of mutant proteins, we showed that dynamin 2 (DNM2), the small GTPase Rab5 and the endocytosis receptor LDL receptor-related protein 1 (LRP-1), contribute significantly to gefitinib-mediated EGFR endocytosis in glioma cells. Importantly, we showed that inhibition of DNM2 or LRP-1 also decreased glioma cell responsiveness to gefitinib during cell evasion from tumour spheroids. By highlighting the contribution of endocytosis proteins in the activity of gefitinib on glioma cells, this study suggests that endocytosis and membrane trafficking might be an attractive therapeutic target to improve GBM treatment.
Mots clés
cell invasion, glioblastoma, membrane trafficking, tyrosine kinase inhibitors
Référence
Cells. 2021 Nov 21;10(11):