Sensitization of TNF-induced cytotoxicity in lung cancer cells by concurrent suppression of the NF-kappaB and Akt pathways

Biochem Biophys Res Commun. 2007 Apr 13;355(3):807-12. doi: 10.1016/j.bbrc.2007.02.030. Epub 2007 Feb 12.


Blockage of either nuclear factor-kappaB (NF-kappaB) or Akt sensitizes cancer cells to TNF-induced apoptosis. In this study, we investigated the undetermined effect of concurrent blockage of these two survival pathways on TNF-induced cytotoxicity in lung cancer cells. The results show that Akt contributes to TNF-induced NF-kappaB activation in lung cancer cells through regulating phosphorylation of the p65/RelA subunit of NF-kappaB. Although individually blocking IKK or Akt partially suppressed TNF-induced NF-kappaB activation, concurrent suppression of these pathways completely inhibited TNF-induced NF-kappaB activation and downstream anti-apoptotic gene expression, and synergistically potentiated TNF-induced cytotoxicity. Moreover, suppression of Akt inhibited the Akt-mediated anti-apoptotic pathway through dephosphorylation of BAD. These results indicate that concurrent suppression of NF-kappaB and Akt synergistically sensitizes TNF-induced cytotoxicity through blockage of distinct survival pathways downstream of NF-kappaB and Akt, which may be applied in lung cancer therapy.

MeSH terms

  • Apoptosis* / genetics
  • Cell Line, Tumor
  • Gene Expression Regulation
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors
  • I-kappa B Kinase / genetics
  • Lung Neoplasms / metabolism*
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Small Interfering / pharmacology
  • Transcription Factor RelA / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology*
  • bcl-Associated Death Protein / metabolism


  • BAD protein, human
  • NF-kappa B
  • RNA, Small Interfering
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • bcl-Associated Death Protein
  • Proto-Oncogene Proteins c-akt
  • I-kappa B Kinase