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Constitutively activated nuclear factor- b, but not induced nf- b, leads to trail resistance by up-regulation of x-linked inhibitor of apoptosis protein in human cancer cells

Braeuer, S. J.
; 
Buneker, C.
; 
Mohr, A.
; 
Zwacka, R. M.
Repository DOI
Publication Date
2006-10-01
Keywords
pancreatic adenocarcinoma cells, ligand-mediated apoptosis, fadd-dependent apoptosis, drug-induced apoptosis, down-regulation, prostate-cancer, melanoma-cells, death domain, tumor-cells, caspase-8 activation
Type
Article
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Citation
Braeuer, S. J. Buneker, C.; Mohr, A.; Zwacka, R. M. (2006). Constitutively activated nuclear factor- b, but not induced nf- b, leads to trail resistance by up-regulation of x-linked inhibitor of apoptosis protein in human cancer cells. Molecular Cancer Research 4 (10), 715-728
Abstract
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.
Funder
Publisher
American Association for Cancer Research (AACR)
Publisher DOI
10.1158/1541-7786.mcr-05-0231
Rights
Attribution-NonCommercial-NoDerivs 3.0 Ireland
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Externally hosted open access publications with University of Galway authors (1)