The AKT/IκB kinase pathway promotes angiogenic/metastatic gene expression in colorectal cancer by activating nuclear factor-κB and β-catenin

Our laboratory has delineated that the phosphatidylinositol 3′ kinase (PI3K)/AKT/I κ B kinase (IKK) pathway positively regulates NF κ B and β -catenin, both important transcriptional regulators in colorectal cancer (CRC). Therefore, we investigated the effect of inhibiting the PI3K/AKT/IKK α pathway in regulating the inappropriate constitutive activation of NF κ B and β -catenin in CRC cell lines. SW480 and RKO CRC cell lines demonstrate constitutive activation of AKT as well as both NF κ B- and β -catenin-dependent transcription. The constitutive activation of NF κ B- and β -catenin-dependent transcription is inhibited by transiently transfecting either kinase dead (KD) IKK α , which blocks IKK α kinase activity, KD AKT, which blocks AKT activity, or wildtype (WT) PTEN, which inhibits PI3K and AKT activity. The ability of KD IKK α , KD AKT or WT PTEN to decrease β -catenin-dependent transcription is independent of their effects on NF κ B. Inducible expression of either KD IKK α or WT PTEN strongly inhibits both the constitutive NF κ B- and β -catenin-dependent promoter and endogenous gene activation. Targeted array-based gene expression analysis of this inducible system reveals that many of the genes downregulated upon inhibition of this pathway are involved in tumor angiogenesis and metastasis. The activation of this pathway and the expression of the three most repressed genes was further analysed in samples of CRC. These results indicate a role of this pathway in controlling gene expression important in tumor progression and metastasis.