c-Rel is a critical mediator of NF-kappa B-dependent TRAIL resistance of pancreatic cancer cells

Geismann, C., Grohmann, F., Sebens, S., Wirths, G., Dreher, A., Haesler, R., Rosenstiel, Philip, Hauser, C., Egberts, J. H., Trauzold, A., Schneider, G., Sipos, B., Zeissig, S., Schreiber, Stefan, Schaefer, H. and Arlt, A. (2014) c-Rel is a critical mediator of NF-kappa B-dependent TRAIL resistance of pancreatic cancer cells Cell Death & Disease, 5 . DOI 10.1038/cddis.2014.417.

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest malignancies with an overall life expectancy of 6 months despite current therapies. NF-kappa B signalling has been shown to be critical for this profound cell-autonomous resistance against chemotherapeutic drugs and death receptor-induced apoptosis, but little is known about the role of the c-Rel subunit in solid cancer and PDAC apoptosis control. In the present study, by analysis of genome-wide patterns of c-Rel-dependent gene expression, we were able to establish c-Rel as a critical regulator of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in PDAC. TRAIL-resistant cells exhibited a strong TRAIL-inducible NF-kappa B activity, whereas TRAIL-sensitive cells displayed only a small increase in NF-kappa B-binding activity. Transfection with siRNA against c-Rel sensitized the TRAIL-resistant cells in a manner comparable to siRNA targeting the p65/RelA subunit. Gel-shift analysis revealed that c-Rel is part of the TRAIL-inducible NF-kappa B complex in PDAC. Array analysis identified NFATc2 as a c-Rel target gene among the 12 strongest TRAIL-inducible genes in apoptosis-resistant cells. In line, siRNA targeting c-Rel strongly reduced TRAIL-induced NFATc2 activity in TRAIL-resistant PDAC cells. Furthermore, siRNA targeting NFATc2 sensitized these PDAC cells against TRAIL-induced apoptosis. Finally, TRAIL-induced expression of COX-2 was diminished through siRNA targeting c-Rel or NFATc2 and pharmacologic inhibition of COX-2 with celecoxib or siRNA targeting COX-2, enhanced TRAIL apoptosis. In conclusion, we were able to delineate a novel c-Rel-, NFATc2- and COX-2-dependent antiapoptotic signalling pathway in PDAC with broad clinical implications for pharmaceutical intervention strategies.

Document Type: Article
Additional Information: Times Cited: 0 Hasler, Robert/A-4908-2009; Trauzold, Anna/P-4398-2014 0
Keywords: Cancer therapeutic resistanceNF-kappaBPancreatic cancer
Research affiliation: Kiel University > Kiel Marine Science
OceanRep > The Future Ocean - Cluster of Excellence
Kiel University
Refereed: Yes
DOI etc.: 10.1038/cddis.2014.417
ISSN: 2041-4889
Projects: Future Ocean
Date Deposited: 30 Mar 2015 12:14
Last Modified: 24 Sep 2019 03:49
URI: http://eprints.uni-kiel.de/id/eprint/27541

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