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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2014-10

AUTHORS

C Geismann, F Grohmann, S Sebens, G Wirths, A Dreher, R Häsler, P Rosenstiel, C Hauser, J-H Egberts, A Trauzold, G Schneider, B Sipos, S Zeissig, S Schreiber, H Schäfer, A Arlt

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. More... »

PAGES

e1455

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/cddis.2014.417

    DOI

    http://dx.doi.org/10.1038/cddis.2014.417

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1011782198

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/25299780


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