Butyrate‐treated colonic Caco‐2 cells exhibit defective integrin‐mediated signaling together with increased apoptosis and differentiation

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Abstract
We previously reported that the enterocytic differentiation of human colonic Caco‐2 cells correlated with alterations in integrin signaling. We now investigated whether differentiation and apoptosis of Caco‐2 cells induced by the short‐chain fatty acid butyrate (NaBT) was associated with alterations in the integrin‐mediated signaling pathway with special interest in the expression and activity of focal adhesion kinase (FAK), of the downstream phosphatidylinositol 3′‐kinase (PI 3‐kinase)–Akt pathway and in the role of the nuclear factor κB (NF‐κB). NaBT increased the level of sucrase. It induced apoptosis as shown by: (1) decreased Bcl‐2 and Bcl‐XL proteins and increased Bax protein; (2) activation of caspase‐3; and (3) increased shedding of apoptotic cells in the medium. This effect was associated with defective integrin‐mediated signaling as shown by: (1) down‐regulation of β1 integrin expression; 2) decreased FAK expression and tyrosine phosphorylation; (3) concerted alterations in cytoskeletal and structural focal adhesions proteins (talin, ezrin); and (4) decreased FAK ability to associate with PI 3‐kinase. However, in Caco‐2 cells, β1‐mediated signaling failed to be activated downstream of FAK and PI 3‐kinase at the level of Akt. Transfection studies show that NaBT treatment of Caco‐2 cells promoted a significant activation of the NF‐κB which was probably involved in the NaBT‐induced apoptosis. Our results indicate that the prodifferentiating agent NaBT induced apoptosis of Caco‐2 cells probably through NF‐κB activation together with a defective β1 integrin‐FAK‐PI 3‐kinase pathways signaling. J. Cell. Physiol. 197: 336–347, 2003