Cell detachment triggers p38 mitogen-activated protein kinase-dependent overexpression of Fas ligand. A novel mechanism of Anoikis of intestinal epithelial cells

Many cell types undergo apoptosis when they are detached from the extracellular matrix (ECM). This phenomenon has been termed anoikis. Most epithelial cells, which are normally attached to a type of ECM called basement membrane, are particularly sensitive to anoikis. Conversely, carcinoma cells tend to be resistant to anoikis, and this resistance plays a critical role in tumor invasion and metastasis. We reported previously that detachment-induced down-regulation of the anti-apoptotic molecule Bcl-X(L) makes a significant contribution to anoikis of intestinal epithelial cells. Here we demonstrate that exogenous Bcl-X(L), no matter how highly expressed in these cells, can significantly attenuate anoikis but cannot completely prevent it, suggesting that at least another pro-apoptotic event is activated by the loss of cell-ECM contacts. Indeed, in this study we identified a novel mechanism of anoikis in intestinal epithelial cells that involves detachment-induced overexpression of Fas ligand. We also demonstrated that this elevation in Fas ligand expression requires a detachment-induced increase of p38 mitogen-activated protein kinase activity. We conclude that the activation of at least two different pro-apoptotic events is required for anoikis of intestinal epithelial cells.