Abstract
Our laboratory has delineated that the phosphatidylinositol 3′ kinase (PI3K)/AKT/IκB kinase (IKK) pathway positively regulates NFκB and β-catenin, both important transcriptional regulators in colorectal cancer (CRC). Therefore, we investigated the effect of inhibiting the PI3K/AKT/IKKα pathway in regulating the inappropriate constitutive activation of NFκB and β-catenin in CRC cell lines. SW480 and RKO CRC cell lines demonstrate constitutive activation of AKT as well as both NFκB- and β-catenin-dependent transcription. The constitutive activation of NFκB- and β-catenin-dependent transcription is inhibited by transiently transfecting either kinase dead (KD) IKKα, which blocks IKKα kinase activity, KD AKT, which blocks AKT activity, or wildtype (WT) PTEN, which inhibits PI3K and AKT activity. The ability of KD IKKα, KD AKT or WT PTEN to decrease β-catenin-dependent transcription is independent of their effects on NFκB. Inducible expression of either KD IKKα or WT PTEN strongly inhibits both the constitutive NFκB- 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.
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Abbreviations
- NF-κB:
-
nuclear factor kappa B
- PI3K:
-
phosphatidylinositol 3′ kinase
- IKK:
-
IκB kinase
- CRC:
-
colorectal cancer
- KD:
-
kinase dead
- WT:
-
wild type
- APC:
-
adenomatous polyposis coli
- GSK3β:
-
glycogen synthase kinase 3β
- TNF:
-
tumor necrosis factor
- IκBs:
-
inhibitors of NFκB
- MEFs:
-
mouse embryo fibroblasts
- TCF:
-
T-cell factor
- LEF:
-
lymphoid-enhancer factor
- IL-1:
-
interleukin-1
- HA:
-
hemagglutinin
- GFP:
-
green fluorescent protein
- IκBαSR:
-
IκBα super repressor
- LY 294 002:
-
LY
- IL-8:
-
interleukin-8
- uPA:
-
urokinase-type plasminogen activator
- PAI-1:
-
plasminogen activator inhibitor-1
- EGF:
-
epidermal growth factor
- VEGF:
-
vascular endothelial growth factor
- TGFα:
-
transforming growth factor-α
- COX2:
-
cyclooxygenase 2
- MMP:
-
matrix metalloproteinase
- PN:
-
ponasterone A
- GAPDH:
-
glyceraldehyde phosphodehydrogenase
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Acknowledgements
We thank David Donner, Julian Downward, Kenneth W Kinzler, Bert Vogelstein, Bryan Williams, and Kenneth Yamada for the various reagents used for this work. This work was supported by grants to NS from the NIH (R01 CA 100748), Case Western Reserve University Comprehensive Cancer Center, the American Cancer Society, and the Ohio Cancer Research Associates.
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Agarwal, A., Das, K., Lerner, N. et al. The AKT/IκB kinase pathway promotes angiogenic/metastatic gene expression in colorectal cancer by activating nuclear factor-κB and β-catenin. Oncogene 24, 1021–1031 (2005). https://doi.org/10.1038/sj.onc.1208296
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DOI: https://doi.org/10.1038/sj.onc.1208296
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