Journal
MOLECULAR CANCER RESEARCH
Volume 4, Issue 10, Pages 715-728Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-05-0231
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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-kappa B (NF-kappa B) 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-kappa B in all our cancer cell lines regardless of their TRAIL sensitivity. Inhibition of NF-kappa B via adenoviral expression of the I kappa B-alpha super-repressor only sensitized the TRAIL-resistant pancreatic cancer cell line Panc-1. Panc-1 cells harbor constitutively activated NF-kappa B, pointing to a possible role of preactivated NF-kappa B in protection front TRAIL. Furthermore, we could reduce X-linked inhibitor of apoptosis protein (XIAP) levels in Panc-1 cells by inhibition of constitutively activated NF-kappa B and sensitize Panc-1 cells to TRAIL by RNA interference against XIAP. These results implicate elevated XIAP levels caused by high basal NF-kappa B activity in TRAIL resistance and suggest that therapeutic strategies involving TRAIL can be abetted by inhibition of NF-kappa B and/or XIAP only in tumor cells with constitutively activated NF-kappa B.
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