Transforming growth factor-alpha prevents detachment-induced inhibition ofc-Src kinase activity, Bcl-X-L down-regulation, and apoptosis of intestinal epithelial cells

Detachment of epithelial cells from the extracellular matrix (ECM) results in apoptosis, a phenomenon often referred to as anoikis. Acquisition of ano ikis resistance is now thought to be a prerequisite for the progression of carcinomas. Colorectal cancer cells frequently secrete epidermal growth fac tor receptor (EGFR) ligands, which are known to have anti-apoptotic activit y. However, whether these ligands have the ability to inhibit anoikis of in testinal epithelial cells is unclear, since at least in some cell types eff icient EGFR signaling requires cell-ECM adhesion. Here we report that trans forming growth factor-alpha (TGF-alpha), an EGFR ligand that is frequently secreted by colorectal cancer cells, strongly inhibits anoikis of the non-m alignant rat intestinal epithelial cell lines, IEC-18 and RIE-1. TGF-alpha exerts its anti-anoikis effect by preventing detachment-induced inhibition of c-Src kinase activity. We also show that Fas activation, a molecular eve nt known to play a critical role in anoikis, is not suppressed by TGF-alpha . On the other hand, this growth factor strongly inhibits the detachment-in duced down-regulation of Bcl-X-L, another change that is involved in the in duction of anoikis. We further demonstrate that this inhibition occurs in a c-Src-dependent manner. We conclude that TGF-a has the ability to suppress anoikis of intestinal epithelial cells, at least in part, by reverting the loss of c-Src activity and Bcl-X-L expression induced by detachment from t he ECM.