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

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.

The proteasome inhibitor PS-341 overcomes TRAIL resistance in Bax and caspase 9-negative or Bcl-xL overexpressing cells

“…The ability of proteasome inhibitors, including PS-341, to stimulate TRAIL-induced apoptosis has also been reported in other cell lines (Mitsiades et al, 2001;Franco et al, 2001). The effects of TRAIL on induction of apoptosis in human prostate cancer cells are known to be blocked by overexpression of Bcl-2 or Bcl-xL (Munshi et al, 2001;Roklin et al, 2001).…”

Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression

“…A general role of transcription factor NF-κB in protection against TRAIL-mediated apoptosis is well known [39,40]. Interestingly, soluble TRAIL (50 ng/ml) rapidly induced phospho-IκBα degradation in LU1205 melanoma cells (data not shown), which was accompanied by rapid induction of NF-κB DNA-binding activity.…”

Proteasome inhibitor PS-341 causes cell growth arrest and apoptosis in human glioblastoma multiforme (GBM)

“…Both TRAIL and TNFa can bind to their respective receptors, and activate the caspase apoptotic pathway, as well as, stimulate NF-kB activation (Franco et al, 2001;Dai et al, 2003). Proteasome inhibitors can block the stimulation of NF-kB while leaving the activation of the caspase pathway intact, explaining that PS-341 may enhance TNFa and TRAIL cell death (Franco et al, 2001;An et al, 2003) (Figure 11). In our studies, PS-341 markedly increased apoptosis of the GBM cell lines treated with either TNFa or TRAIL, suggesting that PS-341 may be a clinically useful adjunct to therapy with TRAIL and TNFa-like drugs.…”

“…Previous studies have shown that activation of NF-kB can inhibit apoptosis induced by a number of stimuli (Wang et al, 1998). Both TRAIL and TNFa can bind to their respective receptors, and activate the caspase apoptotic pathway, as well as, stimulate NF-kB activation (Franco et al, 2001;Dai et al, 2003). Proteasome inhibitors can block the stimulation of NF-kB while leaving the activation of the caspase pathway intact, explaining that PS-341 may enhance TNFa and TRAIL cell death (Franco et al, 2001;An et al, 2003) (Figure 11).…”