Constitutively Activated Nuclear Factor-κB, but not Induced NF-κB, Leads to TRAIL Resistance by Up-Regulation of X-Linked Inhibitor of Apoptosis Protein in Human Cancer Cells

<jats:title>Abstract</jats:title><jats:p>The tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in most, but not all, cancer cells. The molecular factors regulating the sensitivity to TRAIL are still incompletely understood. The transcription factor nuclear factor-κB (NF-κB) has been implicated, but its exact role is controversial. We studied different cell lines displaying varying responses to TRAIL and found that TRAIL can activate NF-κB in all our cancer cell lines regardless of their TRAIL sensitivity. Inhibition of NF-κB via adenoviral expression of the IκB-α super-repressor only sensitized the TRAIL-resistant pancreatic cancer cell line Panc-1. Panc-1 cells harbor constitutively activated NF-κB, pointing to a possible role of preactivated NF-κB in protection from TRAIL. Furthermore, we could reduce X-linked inhibitor of apoptosis protein (XIAP) levels in Panc-1 cells by inhibition of constitutively activated NF-κB and sensitize Panc-1 cells to TRAIL by RNA interference against XIAP. These results implicate elevated XIAP levels caused by high basal NF-κB activity in TRAIL resistance and suggest that therapeutic strategies involving TRAIL can be abetted by inhibition of NF-κB and/or XIAP only in tumor cells with constitutively activated NF-κB. (Mol Cancer Res 2006;4(10):715–28)</jats:p>