Detachment-induced upregulation of XIAP and cIAP2 delays anoikis of intestinal epithelial cells

Detachment of normal epithelial cells from the extracellular matrix triggers apoptosis, a phenomenon called anoikis. Conversely, carcinoma cells tend to be relatively more anoikis- resistant than their normal counterparts, and this increased resistance represents a critical feature of the malignant phenotype. Mechanisms that control susceptibilityand resistance to anoikis are not fully understood. It is now known that detachment of non-malignant epithelial cells triggers both pro- and antiapoptotic signals, and it is the balance between these signals and the duration of detachment that determine further fate of the cells. Detachment- induced antiapoptotic events delay anoikis and if cells reattach relativelysoo n after detachment they survive. Direct regulators of apoptosis responsible for this delay of anoikis are unknown. We found that detachment of non-malignant intestinal epithelial cells triggers upregulation of inhibitors of apoptosis protein (IAP) family, such as X- chromosome- linked inhibitor of apoptosis protein and cellular inhibitor of apoptosis- 2 (cIAP2). We demonstrated that this upregulation requires detachment-dependent activation of the transcription factor nuclear factor-kappa B. We further observed that various IAP antagonists accelerate anoikis, indicating that upregulation of the IAPs delays detachment- triggered apoptosis. We conclude that the IAPs are important regulators of the balance between detachment- triggered life and death signals. Perhaps, not by coincidence, these proteins are often upregulated in carcinomas, tumors composed of cells that tend to be anoikis- resistant.