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Originally published In Press as doi:10.1074/jbc.M106424200 on August 3, 2001

J. Biol. Chem., Vol. 276, Issue 40, 37273-37279, October 5, 2001
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Transforming Growth Factor-alpha Prevents Detachment-induced Inhibition of c-Src Kinase Activity, Bcl-XL Down-regulation, and Apoptosis of Intestinal Epithelial Cells*

Kirill Rosen, Mariano Loza Coll, Alwin Li, and Jorge FilmusDagger

From the Sunnybrook and Women's College Health Sciences Centre, Division of Molecular and Cell Biology, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5 and the Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada

Detachment of epithelial cells from the extracellular matrix (ECM) results in apoptosis, a phenomenon often referred to as anoikis. Acquisition of anoikis resistance is now thought to be a prerequisite for the progression of carcinomas. Colorectal cancer cells frequently secrete epidermal growth factor receptor (EGFR) ligands, which are known to have anti-apoptotic activity. However, whether these ligands have the ability to inhibit anoikis of intestinal epithelial cells is unclear, since at least in some cell types efficient EGFR signaling requires cell-ECM adhesion. Here we report that transforming growth factor-alpha (TGF-alpha ), an EGFR ligand that is frequently secreted by colorectal cancer cells, strongly inhibits anoikis of the non-malignant 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 event 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-induced down-regulation of Bcl-XL, another change that is involved in the induction of anoikis. We further demonstrate that this inhibition occurs in a c-Src-dependent manner. We conclude that TGF-alpha has the ability to suppress anoikis of intestinal epithelial cells, at least in part, by reverting the loss of c-Src activity and Bcl-XL expression induced by detachment from the ECM.

* This work was supported by the National Cancer Institute of Canada.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Sunnybrook and Women's College Health Sciences Center, Division of Molecular and Cell Biology, 2075 Bayview Ave., Toronto, Ontario M4N 3M5, Canada. Tel.: 416-480-6100, ext. 3350; Fax: 416-480-5703; E-mail: filmus@sten.sunnybrook.utoronto.ca.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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