Role of Endocytosis Proteins in Gefitinib-Mediated EGFR Internalisation in Glioma Cells
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 molecul...
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MDPI AG
2021-11-01
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| author | Elisabete Cruz Da Silva Laurence Choulier Jessica Thevenard-Devy Christophe Schneider Philippe Carl Philippe Rondé Stéphane Dedieu Maxime Lehmann |
| author_facet | Elisabete Cruz Da Silva Laurence Choulier Jessica Thevenard-Devy Christophe Schneider Philippe Carl Philippe Rondé Stéphane Dedieu Maxime Lehmann |
| author_sort | Elisabete Cruz Da Silva |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T05:36:36Z |
| format | Article |
| id | doaj.art-ae2c059d68384ea2b227a99f61c7dfd8 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T05:36:36Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
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| spelling | doaj.art-ae2c059d68384ea2b227a99f61c7dfd82023-11-22T22:53:36ZengMDPI AGCells2073-44092021-11-011011325810.3390/cells10113258Role of Endocytosis Proteins in Gefitinib-Mediated EGFR Internalisation in Glioma CellsElisabete Cruz Da Silva0Laurence Choulier1Jessica Thevenard-Devy2Christophe Schneider3Philippe Carl4Philippe Rondé5Stéphane Dedieu6Maxime Lehmann7UMR CNRS 7021, Laboratory of Bioimaging and Pathologies, University of Strasbourg, 67400 Illkirch, FranceUMR CNRS 7021, Laboratory of Bioimaging and Pathologies, University of Strasbourg, 67400 Illkirch, FranceUMR CNRS 7369, Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Université de Reims Champagne Ardenne (URCA), 51687 Reims, FranceUMR CNRS 7369, Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Université de Reims Champagne Ardenne (URCA), 51687 Reims, FranceUMR CNRS 7021, Laboratory of Bioimaging and Pathologies, University of Strasbourg, 67400 Illkirch, FranceUMR CNRS 7021, Laboratory of Bioimaging and Pathologies, University of Strasbourg, 67400 Illkirch, FranceUMR CNRS 7369, Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Université de Reims Champagne Ardenne (URCA), 51687 Reims, FranceUMR CNRS 7021, Laboratory of Bioimaging and Pathologies, University of Strasbourg, 67400 Illkirch, FranceEGFR (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.https://www.mdpi.com/2073-4409/10/11/3258glioblastomacell invasionmembrane traffickingtyrosine kinase inhibitors |
| spellingShingle | Elisabete Cruz Da Silva Laurence Choulier Jessica Thevenard-Devy Christophe Schneider Philippe Carl Philippe Rondé Stéphane Dedieu Maxime Lehmann Role of Endocytosis Proteins in Gefitinib-Mediated EGFR Internalisation in Glioma Cells Cells glioblastoma cell invasion membrane trafficking tyrosine kinase inhibitors |
| title | Role of Endocytosis Proteins in Gefitinib-Mediated EGFR Internalisation in Glioma Cells |
| title_full | Role of Endocytosis Proteins in Gefitinib-Mediated EGFR Internalisation in Glioma Cells |
| title_fullStr | Role of Endocytosis Proteins in Gefitinib-Mediated EGFR Internalisation in Glioma Cells |
| title_full_unstemmed | Role of Endocytosis Proteins in Gefitinib-Mediated EGFR Internalisation in Glioma Cells |
| title_short | Role of Endocytosis Proteins in Gefitinib-Mediated EGFR Internalisation in Glioma Cells |
| title_sort | role of endocytosis proteins in gefitinib mediated egfr internalisation in glioma cells |
| topic | glioblastoma cell invasion membrane trafficking tyrosine kinase inhibitors |
| url | https://www.mdpi.com/2073-4409/10/11/3258 |
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