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

We found that in MCF-7 breast carcinoma cells, PI3K and Akt suppressed a do se-dependent induction of apoptosis by tumor necrosis factor alpha (TNF). P I3K and Akt stimulated NF-kappa B activation in a dose-dependent manner, su ggesting a common link between these two pathways. TNF has been shown to ac tivate both an apoptotic cascade, as web as a cell survival signal through NF-kappa B. PI3K and ART cell survival signaling were correlated with incre ased 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 TN FR signaling-dependent and -independent mechanisms, potentially representin g a mechanism by which Akt functions to suppress apoptosis in cancer. (C) 2 000 Academic Press.