Activation of beta-catenin and PI3K pathways are crucial for the oncogenesis of colorectal cancer (CRC). It remains controversial whether these two pathways function independently or cooperatively in the development and progression of CRC. We showed previously that beta-catenin inhibited NF-kappa B activation by interacting with p65 and this inhibitory interaction involved an unidentified cellular protein. In this study, we found that the PI3K effect on NF-kappa B activity is dependent on the level of beta-catenin in CRC cells. PI3K promoted NF-kappa B activity in the beta-catenin-low RKO cells; whereas it inhibited NF-kappa B activity in the beta-catenin-high HCT116, DLD-1, and SW480 cells. We showed that PI3K is required for the physical interaction and functional inhibition of NF-kappa B by beta-catenin. Inhibition of PI3K released NF-kappa B suppression in beta-catenin-high CRC cells, which conferred these cells with susceptibility to THF alpha- and Fas-induced apoptosis. This is consistent with the observation showing that the level of beta-catenin and activated Akt are both inversely correlated with the expression of Fas, a downstream target of NF-kappa B, in CRC specimens. Mechanistically, the PI3K subunit p85 formed a complex with beta-catenin and NF-kappa B. Inhibition of PI3K disrupted the complex formation, leading to NF-kappa B activation. Our study not only provides new insight into the cross-talk among PI3K, beta-catenin and NF-kappa B signaling pathways but also indicates that targeting PI3K may yield therapeutic efficacy in treating beta-catenin-high CRC. (C) 2013 Elsevier Inc. All rights reserved.