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The Journal of Immunology, 2001, 166: 5337-5345.
Copyright © 2001 by The American Association of Immunologists

The Role of NF-{kappa}B in TNF-Related Apoptosis-Inducing Ligand (TRAIL)-Induced Apoptosis of Melanoma Cells1

Agustin V. Franco, Xu Dong Zhang, Elisabeth Van Berkel, Jayne E. Sanders, Xi Yi Zhang, Wayne D. Thomas, Tam Nguyen and Peter Hersey2

Department of Oncology and Immunology Unit, David Maddison Clinical Sciences Building, Newcastle, New South Wales, Australia

Previous studies have shown that activation of NF-{kappa}B can inhibit apoptosis induced by a number of stimuli. It is also known that TNF-related apoptosis-inducing ligand (TRAIL) can activate NF-{kappa}B 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-{kappa}B 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-{kappa}B, 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-{kappa}B activation was supported by an increase of TRAIL-induced apoptosis in melanoma cells transfected with a degradation-resistant I{kappa}B{alpha}. Furthermore, studies with NF-{kappa}B reporter constructs revealed that the resistance of melanoma lines to TRAIL-induced apoptosis was correlated to activation of NF-{kappa}B in response to TRAIL. TRAIL-resistant sublines that were generated by intermittent exposure to TRAIL were shown to have high levels of activated NF-{kappa}B, and resistance to TRAIL could be reversed by LLnL and by the superrepressor form of I{kappa}B{alpha}. Therefore, these results suggest that activation of NF-{kappa}B by TRAIL plays an important role in resistance of melanoma cells to TRAIL-induced apoptosis and further suggest that inhibitors of NF-{kappa}B may be useful adjuncts in clinical use of TRAIL against melanoma.




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