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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Autores principales:	Elisabete Cruz Da Silva, Laurence Choulier, Jessica Thevenard-Devy, Christophe Schneider, Philippe Carl, Philippe Rondé, Stéphane Dedieu, Maxime Lehmann
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	glioblastoma cell invasion membrane trafficking tyrosine kinase inhibitors Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/ae2c059d68384ea2b227a99f61c7dfd8
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spelling	oai:doaj.org-article:ae2c059d68384ea2b227a99f61c7dfd82021-11-25T17:13:22ZRole of Endocytosis Proteins in Gefitinib-Mediated EGFR Internalisation in Glioma Cells10.3390/cells101132582073-4409https://doaj.org/article/ae2c059d68384ea2b227a99f61c7dfd82021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/3258https://doaj.org/toc/2073-4409EGFR (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.Elisabete Cruz Da SilvaLaurence ChoulierJessica Thevenard-DevyChristophe SchneiderPhilippe CarlPhilippe RondéStéphane DedieuMaxime LehmannMDPI AGarticleglioblastomacell invasionmembrane traffickingtyrosine kinase inhibitorsBiology (General)QH301-705.5ENCells, Vol 10, Iss 3258, p 3258 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	glioblastoma cell invasion membrane trafficking tyrosine kinase inhibitors Biology (General) QH301-705.5
spellingShingle	glioblastoma cell invasion membrane trafficking tyrosine kinase inhibitors Biology (General) QH301-705.5 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
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.
format	article
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
title	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_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_sort	role of endocytosis proteins in gefitinib-mediated egfr internalisation in glioma cells
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/ae2c059d68384ea2b227a99f61c7dfd8
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Role of Endocytosis Proteins in Gefitinib-Mediated EGFR Internalisation in Glioma Cells

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