Gefitinib induces EGFR and α5β1 integrin co-endocytosis in glioblastoma cells.
Brain Neoplasms
/ metabolism
Cell Line, Tumor
Cell Membrane
/ drug effects
Cell Movement
/ drug effects
Endocytosis
/ drug effects
Endosomes
/ metabolism
Epidermal Growth Factor
/ metabolism
ErbB Receptors
/ metabolism
Gefitinib
/ pharmacology
Glioblastoma
/ metabolism
Humans
Integrin alpha5beta1
/ antagonists & inhibitors
Protein Kinase Inhibitors
/ pharmacology
RNA Interference
RNA, Small Interfering
/ metabolism
Adhesion receptors
Brain cancer
Cell migration
Growth factors receptors
Membrane trafficking
Journal
Cellular and molecular life sciences : CMLS
ISSN: 1420-9071
Titre abrégé: Cell Mol Life Sci
Pays: Switzerland
ID NLM: 9705402
Informations de publication
Date de publication:
Mar 2021
Mar 2021
Historique:
received:
02
03
2020
accepted:
16
10
2020
revised:
08
09
2020
pubmed:
6
11
2020
medline:
10
4
2021
entrez:
5
11
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33151388
doi: 10.1007/s00018-020-03686-6
pii: 10.1007/s00018-020-03686-6
doi:
Substances chimiques
Integrin alpha5beta1
0
Protein Kinase Inhibitors
0
RNA, Small Interfering
0
Epidermal Growth Factor
62229-50-9
EGFR protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Gefitinib
S65743JHBS
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2949-2962Subventions
Organisme : Ligue Contre le Cancer
ID : S17R417B
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