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

Abstract

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 Ecadherin-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.

Influence of stress on extracellular matrix and integrin biology

“…This has been described in normal epithelial and endothelial cells, whereas tumor cells are most often resistant to anoıkis (for review, see Frisch and Ruoslahti, 1997). Anoıkis may also be facilitated by the loss of cell-to-cell contacts following dissociation of the cadherin-catenin complexes (Fouquet et al, 2004;Hofmann et al, 2007;Lugo-Martinez et al, 2009). This observation strengthens the notion that anoıkis activation is a more general process for preventing inappropriate cell detachment, and, for this reason, considered as a tumor suppressor mechanism.…”

E-cadherin promotes proliferation of human ovarian cancer cells in vitro via activating MEK/ERK pathway

“…The E-cadherin expression is diminished at later stages of tumor progression as cells de-differentiate and acquire mesenchymal properties associated with a more aggressive phenotype [23][24][25] . Furthermore, a growing volume of data indicate that cell-cell adhesion mediated by E-cadherin is involved in the suppression of anoikis and maintenance of cellular survival in both epithelial cells, such as normal enterocytes [26] , oral squamous carcinoma cells [12] and nonepithelia such as Ewing tumor cells [27] . Instead of distant hematogenous metastasis like most other tumors, regional growth and superficial invasion restricted in the peritoneal cavity are the prominent characteristics of ovarian epithelial cancer.…”

A recombinant matriptase causes an increase in caspase-3 activity in a small-intestinal epithelial IEC-6 line cultured on fibronectin-coated plates

“…*P \ 0.05; N.S. not significant Cytotechnology (2014) 66:357-363 361 of death in SIECs of mice (Fouquet et al 2004). We also found (i) that IEC-6 cells detached as aggregates by treatment with a serine proteases granzyme A and displayed no characteristics of apoptosis (Hirayasu et al 2008) and (ii) that after detachment by treatment with r-MatCD, single IEC-6 cells were mostly positive for annexin-V staining, whereas the ones maintaining cellcell contact (i.e., small cell aggregates) were not (Mochida et al 2010).…”