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Exp Cell Res. 2009 Feb 1;315(3):432-50. doi: 10.1016/j.yexcr.2008.11.003. Epub 2008 Nov 20.

Akt-dependent NF-kappaB activation is required for bile acids to rescue colon cancer cells from stress-induced apoptosis.

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  • 1Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

Abstract

Conjugated secondary bile acids promote human colon cancer cell proliferation by activating EGF receptors (EGFR). We hypothesized that bile acid-induced EGFR activation also mediates cell survival by downstream Akt-regulated activation of NF-kappaB. Deoxycholyltaurine (DCT) treatment attenuated TNF-alpha-induced colon cancer cell apoptosis, and stimulated rapid and sustained NF-kappaB nuclear translocation and transcriptional activity (detected by NF-kappaB binding to an oligonucleotide consensus sequence and by activation of luciferase reporter gene constructs). Both DCT-induced NF-kappaB nuclear translocation and attenuation of TNF-alpha-stimulated apoptosis were dependent on EGFR activation. Inhibitors of nuclear translocation, proteosome activity, and IkappaBalpha kinase attenuated NF-kappaB transcriptional activity. Cell transfection with adenoviral vectors encoding a non-degradable IkappaBalpha 'super-repressor' blocked the actions of DCT on both NF-kappaB activation and TNF-alpha-induced apoptosis. Likewise, transfection with mutant akt and treatment with a chemical inhibitor of Akt attenuated effects of DCT on NF-kappaB transcriptional activity and TNF-alpha-induced apoptosis. Chemical inhibitors of Akt and NF-kappaB activation also attenuated DCT-induced rescue of H508 cells from ultraviolet radiation-induced apoptosis. Collectively, these observations indicate that, downstream of EGFR, bile acid-induced colon cancer cell survival is mediated by Akt-dependent NF-kappaB activation. These findings provide a mechanism whereby bile acids increase resistance of colon cancer to chemotherapy and radiation.

PMID:
19056378
[PubMed - indexed for MEDLINE]
PMCID:
PMC2982790
Free PMC Article

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