Up-regulation of alpha 2 beta 1 integrin cell-surface expression protects A431 cells from epidermal growth factor-induced apoptosis.
High epidermal growth factor (EGF) concentration (10(-8) M) induces inhibition of A431 cell proliferation, resulting in part from an apoptotic process. For some cells escaping this process, proliferation was associated with a decrease in apoptosis. Moreover, these surviving cells displayed marked morphological changes consisting of filopodia formation and cell aggregation. Disrupting cell-cell contacts by lowering extracellular calcium concentration reversed the resistance process, suggesting that apoptosis protection by aggregation may involve intercellular adhesion and cell-cell survival signals probably mediated by calcium-requiring molecules such as integrins. From a panel of integrins tested, only alpha 2 beta 1 integrin cell-surface expression was up-regulated after high apoptotic EGF treatment, and this up-regulation was not observed under a growth-stimulatory EGF concentration (10(-11) M). Double-labeling analysis (alpha 2 beta 1/DNA) implicated alpha 2 beta 1 integrin in the resistance process since 99% of cells that up-regulated alpha 2 beta 1 integrin survived a high dose of EGF. Moreover, the involvement of alpha 2 beta 1 integrin up-regulation in the survival of A431 cells that escape EGF-induced apoptosis was verified using the blocking anti-alpha 2 beta 1 integrin antibody, which was shown to decrease the survival of EGF-stimulated cells. Furthermore, under our culture conditions, alpha 2 beta 1 integrin-dependent cell-cell adhesion can be inhibited without affecting other cell-adhesive interactions, suggesting that alpha 2 beta 1 integrin is involved more directly in cell-cell interaction than in cell-substrate adhesion. Our results provide evidence that EGF-induced up-regulation of alpha 2 beta 1 integrin contributes to the enhancement of cell-cell adhesion, leading to cell aggregate formation, which permits the escape of A431 cells to EGF-induced death by alpha 2 beta 1 integrin signaling.
Smida Rezgui
S
S
Laboratoire de Cancérologie Expérimentale, Faculté de Médecine Nord, Marseille, France. smida.s@jean-roche.univ-mrs.fr
Honore
S
S
Rognoni
J B
JB
Martin
P M
PM
Penel
C
C
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002118:Calcium / Q000494:pharmacology; D020013:Calcium Signaling; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D002449:Cell Aggregation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D006801:Humans; D016023:Integrins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D038981:Receptors, Collagen; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; D016023:Integrins; D009363:Neoplasm Proteins; D038981:Receptors, Collagen; D004815:Epidermal Growth Factor; D002118:Calcium