The role of NF-kappa B in TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis of melanoma cells

• Published in: The Journal of immunology (1950) 2001-05, Vol.166 (9), p.5337-5345
• Main Authors: Franco, A V, Zhang, X D, Van Berkel, E, Sanders, J E, Zhang, X Y, Thomas, W D, Nguyen, T, Hersey, P
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; Apoptosis - genetics; Apoptosis - immunology; Apoptosis Regulatory Proteins; CD40 Ligand - physiology; Cell Culture Techniques; Cell Nucleus - immunology; Cell Nucleus - metabolism; Cysteine Endopeptidases - metabolism; Cytoplasm - immunology; Cytoplasm - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Fas Ligand Protein; Genes, Reporter - immunology; Humans; I-kappa B Proteins; Immunity, Innate - drug effects; Immunity, Innate - genetics; Ligands; Melanoma - enzymology; Melanoma - immunology; Melanoma - pathology; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - physiology; Multienzyme Complexes - antagonists & inhibitors; Multienzyme Complexes - metabolism; NF-kappa B - antagonists & inhibitors; NF-kappa B - genetics; NF-kappa B - metabolism; NF-kappa B - physiology; NF-KappaB Inhibitor alpha; Proteasome Endopeptidase Complex; Repressor Proteins - physiology; TNF-Related Apoptosis-Inducing Ligand; TRAIL protein; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.166.9.5337

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.