Abstract
Abstract NF-κB has been shown to be critical for resistance of pancreatic ductal adenocarcinoma (PDAC) against chemotherapeutic drug and death receptor induced apoptosis, but little is known about the role of the c-Rel subunit. 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 TRAIL induced apoptosis in PDAC. Transfection with siRNA against c-Rel sensitized the TRAIL resistant PDAC cells and EMSA revealed that c-Rel is part of the TRAIL inducible NF-κB complex. Array analysis identified NFATc2 as a critical downstream target of c-Rel in PDAC. In line, siRNA targeting c-Rel strongly reduced TRAIL induced NFATc2 activity and siRNA targeting NFATc2 sensitized PDAC cells against TRAIL induced apoptosis. Finally, TRAIL induced expression of COX-2 was diminished through siRNA targeting c-Rel or NFATc2 and pharmacological inhibition of COX-2 with celecoxib enhanced TRAIL apoptosis. In conclusion, we were able to delineate a novel c-Rel, NFATc2 and COX-2 dependent anti-apoptotic signalling pathway in PDAC with broad clinical implications for pharmaceutical intervention strategies. Citation Format: Claudia Geismann, Frauke Grohmann, Robert Häsler, Philip Rosenstiel, Günter Schneider, Sebastian Zeissig, Stefan Schreiber, Heiner Schäfer, Alexander Arlt. c-Rel is a critical mediator of NF-κB dependent TRAIL resistance of pancreatic cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B114.
Published Version
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