PI3-K/AKT regulation of NF-κB signaling events in suppression of TNF-induced apoptosis

We found that in MCF-7 breast carcinoma cells, PI3K and Akt suppressed a dose-dependent induction of apoptosis by tumor necrosis factor alpha (TNF). PI3K and Akt stimulated NF-kappa B activation in a dose-dependent manner, suggesting a common link between these two pathways. TNF has been shown to activate both an apoptotic cascade, as web as a cell survival signal through NF-kappa B. PI3K and ART cell survival signaling were correlated with increased TNF-stimulated NF-kappa B activity in MCF-7 cells. We demonstrate that while both TNFR1 and NIK are partially involved in Akt-induced NF-kappa B stimulation, a dominant negative I kappa B alpha completely blocked Akt-NF-kappa B cross-talk. PI3K-Akt signaling activated NF-kappa B through both TNFR signaling-dependent and -independent mechanisms, potentially representing a mechanism by which Akt functions to suppress apoptosis in cancer. (C) 2000 Academic Press.