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

Geismann, Claudia, Grohmann, Frauke, Haesler, Robert, Rosenstiel, Philip, Schneider, Guenter, Zeissig, Sebastian, Schreiber, Stefan, Schaefer, Heiner and Arlt, Alexander (2015) c-Rel is a critical mediator of NF-kappa B dependent TRAIL resistance of pancreatic cancer cells Cancer Research, 75 . 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-κB 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-κB activity, whereas TRAIL-sensitive cells displayed only a small increase in NF-κB-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-κB 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 13 AACR Special Conference on Pancreatic Cancer - Innovations in Research and Treatment May 18-21, 2014-2015 New Orleans, LA Amer Assoc Canc Res
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: 0008-5472
Projects: Future Ocean
Date Deposited: 20 Oct 2016 10:50
Last Modified: 21 Jun 2019 13:07
URI: http://eprints.uni-kiel.de/id/eprint/32487

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