Gefitinib induces EGFR and α5β1 integrin co-endocytosis in glioblastoma cells.

Abstract

Overexpression of EGFR drives glioblastomas (GBM) cell invasion but these tumours remain resistant to EGFR-targeted therapies such as tyrosine kinase inhibitors (TKIs). Endocytosis, an important modulator of EGFR function, is often dysregulated in glioma cells and is associated with therapy resistance. However, the impact of TKIs on EGFR endocytosis has never been examined in GBM cells. In the present study, we showed that gefitinib and other tyrosine kinase inhibitors induced EGFR accumulation in early-endosomes as a result of an increased endocytosis. Moreover, TKIs trigger early-endosome re-localization of another membrane receptor, the fibronectin receptor alpha5beta1 integrin, a promising therapeutic target in GBM that regulates physiological EGFR endocytosis and recycling in cancer cells. Super-resolution dSTORM imaging showed a close-proximity between beta1 integrin and EGFR in intracellular membrane compartments of gefitinib-treated cells, suggesting their potential interaction. Interestingly, integrin depletion delayed gefitinib-mediated EGFR endocytosis. Co-endocytosis of EGFR and alpha5beta1 integrin may alter glioma cell response to gefitinib. Using an in vitro model of glioma cell dissemination from spheroid, we showed that alpha5 integrin-depleted cells were more sensitive to TKIs than alpha5-expressing cells. This work provides evidence for the first time that EGFR TKIs can trigger massive EGFR and alpha5beta1 integrin co-endocytosis, which may modulate glioma cell invasiveness under therapeutic treatment.

• Authors: Anne-Florence Blandin, Elisabete Cruz Da Silva, Marie-Cécile Mercier, Oleksandr Glushonkov, Pascal Didier, Stéphane Dedieu, Cristophe Schneider, Jessica Devy, Nelly Etienne-Selloum, Monique Dontenwill, Laurence Choulier, Maxime Lehmann
• Journal: Cellular and molecular life sciences : CMLS (Cell Mol Life Sci) Vol. 78 Issue 6 Pg. 2949-2962 (Mar 2021) ISSN: 1420-9071 [Electronic] Switzerland
• PMID: 33151388 (Publication Type: Journal Article)

Chemical References

• Integrin alpha5beta1
• Protein Kinase Inhibitors
• RNA, Small Interfering
• Epidermal Growth Factor
• EGFR protein, human
• ErbB Receptors
• Gefitinib

Topics

• Brain Neoplasms (metabolism, pathology)
• Cell Line, Tumor
• Cell Membrane (drug effects, metabolism)
• Cell Movement (drug effects)
• Endocytosis (drug effects)
• Endosomes (metabolism)
• Epidermal Growth Factor (metabolism)
• ErbB Receptors (metabolism)
• Gefitinib (pharmacology)
• Glioblastoma (metabolism, pathology)
• Humans
• Integrin alpha5beta1 (antagonists & inhibitors, genetics, metabolism)
• Protein Kinase Inhibitors (pharmacology)
• RNA Interference
• RNA, Small Interfering (metabolism)