title: c-Rel is a critical mediator of NF-κB-dependent TRAIL resistance of pancreatic cancer cells.
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.
authors.affiliation: Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Geismann
authors.affiliation: Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Grohmann
authors.affiliation: Institute for Experimental Medicine, Kiel, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Sebens
authors.affiliation: Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Wirths
authors.affiliation: Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Dreher
authors.affiliation: Institute of Clinical Molecular Biology, Kiel, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Häsler
authors.affiliation: Institute of Clinical Molecular Biology, Kiel, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Rosenstiel
authors.affiliation: Department of Surgery, Kiel, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Hauser
authors.affiliation: Department of Surgery, Kiel, Germany.
authors.forename: J-H
authors.initials: JH
authors.lastname: Egberts
authors.affiliation: Division of Molecular Oncology, Institute for Experimental Cancer Research, Kiel, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Trauzold
authors.affiliation: Technische Universität München, Klinikum rechts der Isar, II. Medizinische Klinik, Munich, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Schneider
authors.affiliation: Institute of Pathology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Sipos
authors.affiliation: Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Zeissig
authors.affiliation: 1] Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany [2] Institute of Clinical Molecular Biology, Kiel, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schreiber
authors.affiliation: Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Schäfer
authors.affiliation: Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Arlt
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D020569:Proto-Oncogene Proteins c-rel; D053221:TNF-Related Apoptosis-Inducing Ligand; D051996:Transcription Factor RelA; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human