NF-kappaB overrides the apoptotic program of TNF receptor 1 but not CD40 in carcinoma cells.
The activation of NF-kappaB and phosphatidylinositol-3 (PI3) kinase by TNF-alpha and TRAIL overrides the pro-apoptotic effects of these ligands in carcinoma cells and hinders their therapeutic application. In this report we show that CD40 ligand, another member of the TNF superfamily, also triggers the activation of these signalling pathways but, importantly, utilises only the PI3 kinase cascade for anti-apoptotic responses, inasmuch as suppression of PI3 kinase but not NF-kappaB sensitises carcinoma cells to CD40L-induced apoptosis. Therefore, NF-kappaB activation does not always confer anti-apoptotic effects. Moreover, no cross-talk between the two pathways was observed, as the specific suppression of PI3 kinase with chemical inhibitors did not influence CD40-mediated IkappaBalpha phosphorylation and degradation or NF-kappaB binding and transactivation. Similarly, whilst suppression of Akt expression by RNA interference sensitised tumour cells to CD40L-induced apoptosis, it had no effect on CD40-mediated IkappaBalpha degradation. These data provide new evidence for the role of NF-kappaB and PI3 kinase/Akt in phenotypic effects mediated by CD40 ligation and highlight differences in the mechanisms by which TNF family members regulate apoptosis in carcinoma cells.
Davies
Clare C
CC
Cancer Research UK Institute for Cancer Studies, The University of Birmingham Medical School, Birmingham B15 2TA, United Kingdom.
Bem
Danai
D
Young
Lawrence S
LS
Eliopoulos
Aristides G
AG
D017209:Apoptosis; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000494:pharmacology; D002277:Carcinoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D015398:Signal Transduction; D014107:Tosyllysine Chloromethyl Ketone / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology
D019013:CD40 Antigens; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D023201:CD40 Ligand; D014107:Tosyllysine Chloromethyl Ketone; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt