In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 2273-2273
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest malignancies with an overall life expectancy of six months despite palliative radio-chemotherapy. The transcription factor NF-κB has been shown to be a critical component of dysregulated transcription factor activity conferring this profound resistance against chemotherapeutic drugs and death receptor induced apoptosis. Despite extensive data on the role of the most abundant NF-κB subunit p65/RelA in PDAC apoptosis control, only little knowledge of the role of the subunit c-Rel in solid cancers exists. In the present study, three pancreatic carcinoma cell lines (Panc1, Patu8988t, MiaPaca2) were analysed for the role of c-Rel in resistance against TRAIL induced apoptosis. TRAIL resistant Panc1 and Patu8988 cells exhibit a strong TRAIL inducible NF-κB activity, whereas TRAIL sensitive MiaPaca2 cells displayed only a small increase in NF-κB binding activity. Transfection with siRNA against the c-Rel subunit of NF-κB sensitized the TRAIL resistant cells in a comparable fashion like siRNA targeting the p65/RelA subunit. Gel shift analysis revealed that together with the p65/RelA subunit, c-Rel is part of the TRAIL inducible NF-κB complex in PDAC. Array analysis results suggested NFATc2 as a c-Rel target gene that is one of the 15 strongest TRAIL inducible genes in apoptosis-resistant Panc1 cells. 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 strongly reduced through siRNA targeting c-Rel or NFATc2 and pharmacological inhibition of COX-2 with celecoxib strongly increased TRAIL apoptosis. In conclusion, c-Rel is a critical mediator of NF-κB dependent anti-apoptotic signalling in PDAC through activation of NFATc2 and COX-2. Citation Format: Claudia Geismann, Frauke Grohmann, Gabriele Wirths, Susanne Sebens, Anita Dreher, Robert Häsler, Sebastian Zeissig, Stefan Schreiber, Philip Rosenstiel, Heiner Schäfer, Alexander Arlt. c-Rel is a critical mediator of NF-κB-dependent apoptosis resistance of pancreatic cancer cells against TRAIL. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2273. doi:10.1158/1538-7445.AM2014-2273
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2014-2273
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2014
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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