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Cell Cycle, Cell Death and Senescence

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

¹ Division of Gene Therapy, University of Ulm, Ulm, Germany and ² National Centre for Biomedical Engineering Science, National University of Ireland Galway, Galway, Ireland

Requests for reprints: Ralf Michael Zwacka, Division of Gene Therapy, University of Ulm, Helmholtzstr. 8/1, 89081 Ulm, Germany. Phone: 49-731-50033617; Fax: 49-731-50033609. E-mail: ralf.zwacka{at}nuigalway.ie

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-B (NF-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-B in all our cancer cell lines regardless of their TRAIL sensitivity. Inhibition of NF-B via adenoviral expression of the IB- super-repressor only sensitized the TRAIL-resistant pancreatic cancer cell line Panc-1. Panc-1 cells harbor constitutively activated NF-B, pointing to a possible role of preactivated NF-B 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-B and sensitize Panc-1 cells to TRAIL by RNA interference against XIAP. These results implicate elevated XIAP levels caused by high basal NF-B activity in TRAIL resistance and suggest that therapeutic strategies involving TRAIL can be abetted by inhibition of NF-B and/or XIAP only in tumor cells with constitutively activated NF-B. (Mol Cancer Res 2006;4(10):715–28)

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