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

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. 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. The intestinal epithelium displays one of the most rapid turnover rates of any mammalian tissue. Enterocytes differentiate from proliferative cells, during their migration along the crypt-to-villus axis (1Gordon J.I. Hermiston M.L. Curr. Opin. Cell Biol. 1994; 6: 795-803Crossref PubMed Scopus (215) Google Scholar). After 2–6 days, these cells reach the villus tip and are shed into the intestinal lumen, with identical morphological features in human and mouse (2Mayhew T.M. Myklebust R. Whybrow A. Jenkins R. Histol. Histopathol. 1999; 14: 257-267PubMed Google Scholar). Apoptosis is thought to play a dual role in the maintenance of homeostasis in this epithelium: 1) at the base of the crypt (3Potten C.S. Am. J. Physiol. 1997; 273: G253-G257PubMed Google Scholar) to control the number of stem cells and 2) in the shedding process of enterocytes at the villus tip by anoikis (1Gordon J.I. Hermiston M.L. Curr. Opin. Cell Biol. 1994; 6: 795-803Crossref PubMed Scopus (215) Google Scholar, 2Mayhew T.M. Myklebust R. Whybrow A. Jenkins R. Histol. Histopathol. 1999; 14: 257-267PubMed Google Scholar, 4Grossmann J. Walther K. Artinger M. Kiessling S. Scholmerich J. Cell Growth 12: 147-155PubMed Google Scholar). Anoikis refers to apoptosis induced by a loss of cell-matrix interactions and was initially described for epithelial and endothelial cells (5Meredith Jr., J.E. Fazeli B. Schwartz M.A. Mol. Biol. Cell. 1993; 4: 953-961Crossref PubMed Scopus (1405) Google Scholar, 6Frisch S.M. Francis H. J. Cell Biol. 1994; 124: 619-626Crossref PubMed Scopus (2788) Google Scholar). Integrins, which act as adhesion receptors, control cell survival in response to extracellular matrix binding and also affect the cellular response to other survival and death signals, thereby controlling the fate of cells as a function of their immediate environment (7Frisch S.M. Screaton R.A. Curr. Opin. Cell Biol. 2001; 13: 555-562Crossref PubMed Scopus (1180) Google Scholar, 8Stupack D.G. Cheresh D.A. J. Cell Sci. 2002; 115: 3729-3738Crossref PubMed Scopus (514) Google Scholar). It has been suggested that cell-cell interactions also control cell survival, particularly via the classical cadherins, a family of transmembrane proteins promoting calcium-dependent cell-cell adhesion. Cadherin homophilic ligation initiates the assembly of large adhesion multimolecular complexes, which are connected to the actin cytoskeleton via proteins of the catenin family (9Steinberg M.S. McNutt P.M. Curr. Opin. Cell Biol. 1999; 11: 554-560Crossref PubMed Scopus (248) Google Scholar). This connection is essential for the stabilization and the strength of cell-cell junctions (10Nagafuchi A. Takeichi M. EMBO J. 1988; 7: 3679-3684Crossref PubMed Scopus (664) Google Scholar). Cadherin engagement also leads to the transduction of intracellular signals (11Pece S. Chiariello M. Murga C. Gutkind J.S. J. Biol. Chem. 1999; 274: 19347-19351Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar, 12Kovacs E.M. Ali R.G. McCormack A.J. Yap A.S. J. Biol. Chem. 2002; 277: 6708-6718Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar) and has been shown to protect squamous carcinoma cells and normal proximal tubular cells from anoikis (13Kantak S.S. Kramer R.H. J. Biol. Chem. 1998; 273: 16953-16961Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar, 14Bergin E. Levine J.S. Koh J.S. Lieberthal W. Am. J. Physiol. 2000; 278: F758-F768Crossref PubMed Google Scholar). The mechanisms controlling normal enterocyte survival are poorly understood. Electron microscopy studies suggest that cell-matrix and cell-cell interactions are disrupted sequentially in enterocytes reaching the villus tip (15Shibahara T. Sato N. Waguri S. Iwanaga T. Nakahara A. Fukutomi H. Uchiyama Y. Arch. Histol. Cytol. 1995; 58: 205-219Crossref PubMed Scopus (92) Google Scholar). Furthermore, loss of E-cadherin function in intestinal epithelium via the targeted expression of a dominant negative N-cadherin mutant increases the frequency of apoptotic cells while perturbing migration and differentiation (16Hermiston M.L. Gordon J.I. J. Cell Biol. 1995; 129: 489-506Crossref PubMed Scopus (385) Google Scholar). We hypothesized that the remodeling of E-cadherin-cytoskeleton complexes upon the loss of anchorage might be involved in the apoptosis signaling cascade. Indeed, we recently showed that the targeting of E-cadherin to the upper lateral membrane and its co-localization with subcortical actin in Caco-2 enterocytic cells are controlled by cell-matrix interactions involving integrins (17Schreider C. Peignon G. Thenet S. Chambaz J. Pincon-Raymond M. J. Cell Sci. 2002; 115: 543-552Crossref PubMed Google Scholar). We tested our hypothesis with an original model of anoikis in normal villus epithelium, in which interactions between epithelial cells and the underlying basement membrane were disrupted while cell-cell interactions were maintained. We found that, upon the loss of anchorage, normal enterocytes executed a strikingly rapid apoptosis program. We provide evidence that the loss of E-cadherin from cell-cell contacts, which occurred via a lysosome/proteasome-dependent degradation pathway, preceded the execution phase of detachment-induced apoptosis. Moreover, modulation of E-cadherin engagement affected the rate of apoptosis, demonstrating that E-cadherin participates in the control of anoikis in villus enterocytes. Cell Isolation and Culture—Intestinal villus epithelium was isolated as entire epithelial linings by a method modified from Perreault and Beaulieu (18Perreault N. Beaulieu J.F. Exp. Cell Res. 1998; 245: 34-42Crossref PubMed Scopus (119) Google Scholar). Adult B6CBA mice were killed by cervical dislocation. The small intestine (jejunum and ileum) was everted; washed in ice-cold phosphate-buffered saline (PBS) 1The abbreviations used are: PBS, phosphate-buffered saline; Z, benzyloxycarbonyl; fmk, fluoromethyl ketone; DAPI, 4′,6-diamidino-2-phenylindole-dihydrochloride; TRITC, tetramethylrhodamine isothiocyanate. containing Ca2+, Mg2+, and 1 g/liter d-glucose (Invitrogen); and into The were in at for of the epithelium from the was induced by and After in ice-cold PBS, the were on a in ice-cold modified containing g/liter and with human and on and at in an containing The of the epithelial was by the of of the cells with an antibody and by the of actin in The villus of this was by crypt were only in linings were isolated in the from mice the human control of the A. M. B. N. T. A. A. A. PubMed Scopus Google and were used as a the were to and the caspase the proteasome or or the lysosome were anti-E-cadherin actin and an antibody We used the and and Electron the epithelial linings were by for 1 at in and in The cells were at in and in The cells were by for at in in and in were with and and with a of was by the of small of in J. B. S. M. 1999; PubMed Scopus Google by in a using a as the Apoptosis was by of The cells were by in ice-cold in and in ice-cold was sequentially in of of and of and for at was on an cell with a and Cell and were of the and a of cells were for apoptosis was by apoptotic on with of was for small or epithelial linings in for the were washed in ice-cold PBS, in and in and were The were sequentially in blocking in and with and in blocking and actin was with and the were with in or with in a 1 The were on a or on a with and protein were from epithelial linings washed in and in The protein were with the protein were to in a and The antibody were and the of and the cells were for at in containing a was by at for The was as the The was with the of for was by and the was as the a protein of and an of was by in and The were sequentially with and in saline containing anti-E-cadherin and actin and with an was used to of The were with a using and E-cadherin epithelial linings were in containing a anti-E-cadherin antibody (11Pece S. Chiariello M. Murga C. Gutkind J.S. J. Biol. Chem. 1999; 274: 19347-19351Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar, R. EMBO J. 4: PubMed Scopus Google or as a or a E-cadherin E.M. Ali R.G. McCormack A.J. Yap A.S. J. Biol. Chem. 2002; 277: 6708-6718Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar) E-cadherin-Fc chimera protein, i.e. mouse E-cadherin to the of human 277: Full Text Full Text PDF PubMed Scopus Google and the cells were to were with In both the cells were with and apoptosis was by apoptotic of Apoptosis by of in the response of normal enterocytes to the loss of anchorage of cell-cell interactions by detaching mouse intestinal villus cells from as entire epithelial using a The of epithelial cells with cell-cell are shown in showed that the epithelial linings were as shown by the of the and the of a and cell-cell interactions basement membrane was the membrane We the of the and the in the intestine J.F. 1997; PubMed Google in the and in the epithelial on along the membrane of epithelial In was to the membrane of enterocytes within the as in human intestine J.F. 1997; PubMed Google Scholar). was to the of the epithelial cells was integrins at their cell with in the epithelial linings were to on or a matrix by cells We the fate of epithelial linings in at of the were normal in as early as of the were or that apoptosis was We that apoptosis was by detachment from the and by by of intestinal at apoptotic were in epithelial cells to the villus within of and of cells as a function of that apoptosis was detachment within and of were and the apoptotic of the cell death program by loss of anchorage and its striking in normal enterocytes. of the which anoikis in epithelial cell S.M. Francis H. J. Cell Biol. 1994; 124: 619-626Crossref PubMed Scopus (2788) Google is in the small sensitivity to anoikis be by overexpression in we used mice the human control of the A. M. B. N. T. A. A. A. PubMed Scopus Google Scholar). Bcl-2 were in enterocytes from mice in from as shown by and Bcl-2 detachment-induced apoptosis The rate of apoptosis was also in the of the of caspase activation in the execution of anoikis. We used to activation of the and and of the and was within as shown by a in the of the with an of the In the of and we any of this The activation of and was within by a in the of the of these and the of the of The activation of and was by and with enterocytes with the most of the that activation was by upon and was by and overexpression activation by and The activation of was also by using an antibody that to a by of the with this antibody epithelial cells in intestine or detachment was in cells a apoptotic The of cells with with the of or villus enterocytes are to cell death within loss of anchorage, and apoptosis is executed in most cells within via a Bcl-2-regulated and caspase-9-dependent pathway. of E-cadherin from during Anoikis and to Apoptosis the of our we also of the epithelial linings We E-cadherin by during anoikis. E-cadherin was and to cell-cell detachment and and in of cells Furthermore, the of E-cadherin and of showed that E-cadherin was lost or at cell-cell in cell that whereas E-cadherin was and in cells apoptotic upper After E-cadherin was in of cells, whereas only of cells were apoptotic the cells cell both an apoptotic and for results suggest that E-cadherin is lost from cell-cell the execution of apoptosis in our We investigated the of apoptosis on the fate of Bcl-2 or the of apoptotic at both and with these on the loss of E-cadherin anoikis. in the of E-cadherin was in enterocytes and by that the loss of E-cadherin at upon apoptosis. the hypothesis that E-cadherin loss at the cell membrane precedes both caspase activation and of the morphological of apoptosis. Apoptosis on the in E-cadherin the fate of E-cadherin in epithelial linings upon loss of anchorage, studies were by of and at detachment of epithelial E-cadherin was in the which actin (10Nagafuchi A. Takeichi M. EMBO J. 1988; 7: 3679-3684Crossref PubMed Scopus (664) Google as in intestine This and our morphological that most of the E-cadherin was in the complexes The of was also in the and its of migration was identical in intestine and in in we a in the of E-cadherin with both the and to only of the of E-cadherin was with studies the of this in E-cadherin was affected by or by Bcl-2 only and of the were The by apoptosis at were at the were It has been shown that during apoptosis, E-cadherin is on its in a and on its extracellular by a K. Cell Differ. 1999; 6: PubMed Scopus Google Scholar, J. R. K. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). In the model of enterocyte anoikis, of was using the or the of E-cadherin one of the of E-cadherin, has also been shown to be by in of apoptosis A. J. B. B. K. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google we degradation upon enterocyte anoikis. In to E-cadherin, was into that were in the This process was by upon and by upon Bcl-2 or Bcl-2 were to to the of from the to the are with a remodeling of the multimolecular complexes that apoptosis is and is E-cadherin during Anoikis via a and results that E-cadherin loss precedes apoptosis and degradation by The proteasome and the lysosome been involved in the degradation of E-cadherin and of other classical complexes are M.A. J. Cell Biol. PubMed Scopus Google Scholar, K. S. J. Biol. Chem. 278: Full Text Full Text PDF PubMed Scopus Google Scholar). We E-cadherin degradation upon enterocyte anoikis via these Anoikis was induced in the of the or in the of the proteasome and E-cadherin were a at which the caspase and the of the E-cadherin with the most showed that cells E-cadherin at cell-cell and in of in epithelial linings This is with studies that the proteasome is for of transmembrane receptors, K. S. J. Biol. Chem. 278: Full Text Full Text PDF PubMed Scopus Google Scholar, R. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). the of apoptotic to of upon The of apoptosis and E-cadherin degradation we the of E-cadherin degradation in the of apoptosis. of the of E-cadherin on investigated anoikis be modulated by E-cadherin adhesion signaling We the anoikis in the of an anti-E-cadherin antibody which the and has been to cell-cell adhesion (11Pece S. Chiariello M. Murga C. Gutkind J.S. J. Biol. Chem. 1999; 274: 19347-19351Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar). of the were apoptotic and a of this was in the of the antibody E-cadherin engagement and intracellular we used a E-cadherin-Fc chimera protein containing the E-cadherin to the This has been shown to act as the of as a to the actin cytoskeleton E.M. Ali R.G. McCormack A.J. Yap A.S. J. Biol. Chem. 2002; 277: 6708-6718Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar). 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The of adhesion is a in the of adhesion at the villus to enterocyte anoikis. E-cadherin has been shown to be involved in the control of cell survival in other of apoptosis, and upon via a involving of the M.A. M.L. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). the original anoikis that cells to be in cell-cell interactions to be to this process S.M. Francis H. J. Cell Biol. 1994; 124: 619-626Crossref PubMed Scopus (2788) Google Scholar). Moreover, cells that the to epithelial for to apoptosis (7Frisch S.M. Screaton R.A. Curr. Opin. Cell Biol. 2001; 13: 555-562Crossref PubMed Scopus (1180) Google Scholar). E-cadherin is during the during the of carcinoma 2002; PubMed Scopus Google Scholar) also in inflammatory bowel disease N. C. A. J. A. N. Am. J. 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