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

• Published in: Cell death & disease 2014-10, Vol.5 (10), p.e1455-e1455
• Main Authors: Geismann, C, Grohmann, F, Sebens, S, Wirths, G, Dreher, A, Häsler, R, Rosenstiel, P, Hauser, C, Egberts, J-H, Trauzold, A, Schneider, G, Sipos, B, Zeissig, S, Schreiber, S, Schäfer, H, Arlt, A
• Format: Article
• Language: English
• Subjects: 631/250/516/1909; 631/67/1059/2326; 631/67/1504/1713; Antibodies; Antineoplastic Agents - pharmacology; Apoptosis; Biochemistry; Biomedical and Life Sciences; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - physiopathology; Cell Biology; Cell Culture; Cell Line, Tumor; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Drug Resistance, Neoplasm; Humans; Immunology; Life Sciences; NF-kappa B - genetics; NF-kappa B - metabolism; NFATC Transcription Factors - genetics; NFATC Transcription Factors - metabolism; Original; original-article; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - physiopathology; Proto-Oncogene Proteins c-rel - genetics; Proto-Oncogene Proteins c-rel - metabolism; TNF-Related Apoptosis-Inducing Ligand - metabolism; Transcription Factor RelA - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2014.417

Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest malignancies with an overall life expectancy of 6 months despite current therapies. NF- κ 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- κ B activity, whereas TRAIL-sensitive cells displayed only a small increase in NF- κ 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- κ 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.