期刊
ONCOGENE
卷 24, 期 6, 页码 1021-1031出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1208296
关键词
AKT; PTEN; I kappa B kinase; nuclear factor-kappa B; beta-catenin; colorectal cancer
资金
- NCI NIH HHS [R01 CA100748] Funding Source: Medline
Our laboratory has delineated that the phosphatidylinositol 30 kinase (PI3K)/AKT/IkappaB kinase (IKK) pathway positively regulates NFkappaB and beta-catenin, both important transcriptional regulators in colorectal cancer (CRC). Therefore, we investigated the effect of inhibiting the PI3K/AKT/IKKalpha pathway in regulating the inappropriate constitutive activation of NFkappaB and beta-catenin in CRC cell lines. SW480 and RKO CRC cell lines demonstrate constitutive activation of AKT as well as both NFkappaB- and beta-catenin-dependent transcription. The constitutive activation of NFkappaB- and beta-catenin-dependent transcription is inhibited by transiently transfecting either kinase dead (KD) IKKalpha, which blocks IKKalpha kinase activity, KD AKT, which blocks AKT activity, or wildtype (WT) PTEN, which inhibits PI3K and AKT activity. The ability of KD IKKalpha, KD AKT or WT PTEN to decrease beta-catenin-dependent transcription is independent of their effects on NFkappaB. Inducible expression of either KD IKKalpha or WT PTEN strongly inhibits both the constitutive NFkappaB- and beta-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.
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