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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Active Transport, Cell Nucleus
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Apoptosis / radiation effects
  • Bile Acids and Salts / pharmacology
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Chromones / pharmacology
  • Colonic Neoplasms
  • ErbB Receptors / metabolism
  • Humans
  • I-kappa B Kinase / metabolism
  • Leupeptins / pharmacology
  • Morpholines / pharmacology
  • Mutation
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Nitriles / pharmacology
  • Peptides / pharmacology
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / physiology*
  • Sulfones / pharmacology
  • Taurodeoxycholic Acid / pharmacology*
  • Tumor Necrosis Factor-alpha / pharmacology
  • Ultraviolet Rays


  • 3-(4-methylphenylsulfonyl)-2-propenenitrile
  • Bile Acids and Salts
  • Chromones
  • Leupeptins
  • Morpholines
  • NF-kappa B
  • Nitriles
  • Peptides
  • SN50 peptide
  • Sulfones
  • Tumor Necrosis Factor-alpha
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Taurodeoxycholic Acid
  • EGFR protein, human
  • ErbB Receptors
  • Proto-Oncogene Proteins c-akt
  • I-kappa B Kinase
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde