Constitutively activated nuclear factor-kappaB, but not induced NF-kappaB, leads to TRAIL resistance by up-regulation of X-linked inhibitor of apoptosis protein in human cancer cells.
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-kappaB (NF-kappaB) 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-kappaB in all our cancer cell lines regardless of their TRAIL sensitivity. Inhibition of NF-kappaB via adenoviral expression of the IkappaB-alpha super-repressor only sensitized the TRAIL-resistant pancreatic cancer cell line Panc-1. Panc-1 cells harbor constitutively activated NF-kappaB, pointing to a possible role of preactivated NF-kappaB 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-kappaB and sensitize Panc-1 cells to TRAIL by RNA interference against XIAP. These results implicate elevated XIAP levels caused by high basal NF-kappaB activity in TRAIL resistance and suggest that therapeutic strategies involving TRAIL can be abetted by inhibition of NF-kappaB and/or XIAP only in tumor cells with constitutively activated NF-kappaB.
Braeuer
Susanne J
SJ
Division of Gene Therapy, University of Ulm, Helmholtzstr. 8/1, 89081 Ulm, Germany.
Büneker
Chirlei
C
Mohr
Andrea
A
Zwacka
Ralf Michael
RM
D017209:Apoptosis; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
D020672:I-kappa B Proteins; D016328:NF-kappa B; D053221:TNF-Related Apoptosis-Inducing Ligand; D051636:X-Linked Inhibitor of Apoptosis Protein