Early loss of E-cadherin from cell-cell contacts is involved in the onset of Anoikis in enterocytes

被引:122
作者
Fouquet, S
Lugo-Martínez, VH
Faussat, AM
Renaud, F
Cardot, P
Chambaz, J
Pinçon-Raymond, M
Thenet, S
机构
[1] EPHE, Pharmacol Cellulaire & Mol Lab, UMR INSERM UPMC 505, F-75006 Paris, France
[2] IFR 58, INSERM, EPI9912, F-75006 Paris, France
[3] Univ Versailles, Ecole Prat Hautes Etud, Lab Genet Mol & Physiol, CNRS,UPRESA 8087, F-78000 Versailles, France
关键词
D O I
10.1074/jbc.M405095200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页码:43061 / 43069
页数:9
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