Up-regulation of alpha 2 beta 1 integrin cell-surface expression protects A431 cells from epidermal growth factor-induced apoptosis

• Published in: International journal of cancer 2000-08, Vol.87 (3), p.360-367
• Main Authors: Smida Rezgui, S, Honore, S, Rognoni, J B, Martin, P M, Penel, C
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal - pharmacology; Apoptosis - drug effects; Apoptosis - genetics; Calcium - pharmacology; Calcium Signaling; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Cell Adhesion - drug effects; Cell Aggregation - drug effects; Cell Size - drug effects; Epidermal Growth Factor - pharmacology; Humans; Integrins - biosynthesis; Integrins - genetics; Integrins - immunology; Integrins - physiology; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Neoplasm Proteins - immunology; Neoplasm Proteins - physiology; Receptors, Collagen; Tumor Cells, Cultured; Up-Regulation
• ISSN: 0020-7136
• DOI: 10.1002/1097-0215(20000801)87:3<360::AID-IJC8>3.0.CO;2-9

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.