The Role of NF-κB in TNF-Related Apoptosis-Inducing Ligand (TRAIL)-Induced Apoptosis of Melanoma Cells

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