The role of NF-kappa B in TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis of melanoma cells.
Previous studies have shown that activation of NF-kappaB can inhibit apoptosis induced by a number of stimuli. It is also known that TNF-related apoptosis-inducing ligand (TRAIL) can activate NF-kappaB through the death receptors TRAIL-R1 and TRAIL-R2, and decoy receptor TRAIL-R4. In view of these findings, we have investigated the extent to which activation of NF-kappaB may account for the variable responses of melanoma lines to apoptosis induced by TRAIL and other TNF family members. Pretreatment of the melanoma lines with the proteasome inhibitor N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal (LLnL), which is known to inhibit activation of NF-kappaB, was shown to markedly increase apoptosis in 10 of 12 melanoma lines with death receptors for TRAIL. The specificity of results for inhibition of NF-kappaB activation was supported by an increase of TRAIL-induced apoptosis in melanoma cells transfected with a degradation-resistant IkappaBalpha. Furthermore, studies with NF-kappaB reporter constructs revealed that the resistance of melanoma lines to TRAIL-induced apoptosis was correlated to activation of NF-kappaB in response to TRAIL. TRAIL-resistant sublines that were generated by intermittent exposure to TRAIL were shown to have high levels of activated NF-kappaB, and resistance to TRAIL could be reversed by LLnL and by the superrepressor form of IkappaBalpha. Therefore, these results suggest that activation of NF-kappaB by TRAIL plays an important role in resistance of melanoma cells to TRAIL-induced apoptosis and further suggest that inhibitors of NF-kappaB may be useful adjuncts in clinical use of TRAIL against melanoma.
Franco
A V
AV
Department of Oncology and Immunology Unit, David Maddison Clinical Sciences Building, Newcastle, New South Wales, Australia.
Zhang
X D
XD
Van Berkel
E
E
Sanders
J E
JE
Zhang
X Y
XY
Thomas
W D
WD
Nguyen
T
T
Hersey
P
P
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D023201:CD40 Ligand / Q000502:physiology; D018929:Cell Culture Techniques; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003593:Cytoplasm / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D053222:Fas Ligand Protein; D017930:Genes, Reporter / Q000276:immunology; D006801:Humans; D020672:I-kappa B Proteins; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics; D008024:Ligands; D008545:Melanoma / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex; D012097:Repressor Proteins / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D020672:I-kappa B Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D009097:Multienzyme Complexes; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D012097:Repressor Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D023201:CD40 Ligand; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex