Sensitization of TNF-induced cytotoxicity in lung cancer cells by concurrent suppression of the NF-kappaB and Akt pathways.
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.
Wang
Xia
X
Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM 87108, USA.
Chen
Wenshu
W
Lin
Yong
Y
D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics; D008175:Lung Neoplasms / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D051025:bcl-Associated Death Protein / Q000378:metabolism
C494819:BAD protein, human; D016328:NF-kappa B; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D051025:bcl-Associated Death Protein; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase