Up-regulation of α2β1 integrin cell-surface expresssion protects A431 cells from epidermal growth factor-induced apoptosis

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Abstract
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 α2β1 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 (α2β1/DNA) implicated α2β1 integrin in the resistance process since 99% of cells that up‐regulated α2β1 integrin survived a high dose of EGF. Moreover, the involvement of α2β1 integrin up‐regulation in the survival of A431 cells that escape EGF‐induced apoptosis was verified using the blocking anti‐α2β1 integrin antibody, which was shown to decrease the survival of EGF‐stimulated cells. Furthermore, under our culture conditions, α2β1 integrin–dependent cell–cell adhesion can be inhibited without affecting other cell‐adhesive interactions, suggesting that α2β1 integrin is involved more directly in cell–cell interaction than in cell–substrate adhesion. Our results provide evidence that EGF‐induced up‐regulation of α2β1 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 α2β1 integrin signaling. Int. J. Cancer 87:360–367, 2000.