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J. Biol. Chem., Vol. 279, Issue 41, 43061-43069, October 8, 2004

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Early Loss of E-cadherin from Cell-Cell Contacts Is Involved in the Onset of Anoikis in Enterocytes^*

Stéphane Fouquet, Verónica-Haydée Lugo-Martínez, Anne-Marie Faussat¶, Flore Renaud||, Philippe Cardot, Jean Chambaz, Martine Pinçon-Raymond, and Sophie Thenet**

From the UMR 505 INSERM-UPMC, Laboratoire de Pharmacologie Cellulaire et Moléculaire de l'EPHE, 75006 Paris, France, ^¶INSERM EPI9912, IFR 58, 75006 Paris, France, and ^||CNRS UPRES-A 8087, Laboratoire de Génétique Moléculaire et Physiologique de l'Ecole Pratique des Hautes Etudes, Université de Versailles/Saint Quentin-en-Yvelines, 78000 Versailles, France

Anoikis, i.e. apoptosis induced by detachment from the extracellular matrix, is thought to be involved in the shedding of enterocytes at the tip of intestinal villi. Mechanisms controlling enterocyte survival are poorly understood. We investigated the role of E-cadherin, a key protein of cell-cell adhesion, in the control of anoikis of normal intestinal epithelial cells, by detaching murine villus epithelial cells from the underlying basement membrane while preserving cell-cell interactions. We show that upon the loss of anchorage, normal enterocytes execute a program of apoptosis within minutes, via a Bcl-2-regulated and caspase-9-dependent pathway. E-cadherin is lost early from cell-cell contacts. This process precedes the execution phase of detachment-induced apoptosis as it is only weakly modulated by Bcl-2 overexpression or caspase inhibition. E-cadherin loss, however, is efficiently prevented by lysosome and proteasome inhibitors. We also found that a blocking anti-E-cadherin antibody increases the rate of anoikis, whereas the activation of E-cadherin using E-cadherin-Fc chimera proteins reduces anoikis. In conclusion, our results stress the striking sensitivity of normal enterocytes to the loss of anchorage and the contribution of E-cadherin to the control of their survival/apoptosis balance. They open new perspectives on the key role of this protein, which is dysregulated in the intestinal epithelium in both inflammatory bowel disease and cancer.

Received for publication, May 7, 2004 , and in revised form, July 19, 2004.

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

Supported by the Association François Aupetit.

^** To whom correspondence should be addressed: EPHE-INSERM U505, 15 rue de l'Ecole de Médecine, 75006 Paris, France. Tel.: 33-1-42-34-69-34; Fax: 33-1-43-25-16-15; E-mail: Sophie.Thenet-u505{at}bhdc.jussieu.fr.

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