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Type: Journal article
Title: Sulindac activates NF-κB signaling in colon cancer cells
Other Titles: Sulindac activates NF-kappaB signaling in colon cancer cells
Author: Mladenova, D.
Pangon, L.
Currey, N.
Ng, I.
Musgrove, E.
Grey, S.
Kohonen-Corish, M.
Citation: Cell Communication and Signaling, 2013; 11(1):73-1-73-16
Publisher: BioMed Central
Issue Date: 2013
ISSN: 1478-811X
Statement of
Dessislava Mladenova, Laurent Pangon, Nicola Currey, Irvin Ng, Elizabeth A Musgrove, Shane T Grey and Maija RJ Kohonen-Corish
Abstract: The non-steroidal anti-inflammatory drug (NSAID) sulindac has shown efficacy in preventing colorectal cancer. This potent anti-tumorigenic effect is mediated through multiple cellular pathways but is also accompanied by gastrointestinal side effects, such as colon inflammation. We have recently shown that sulindac can cause up-regulation of pro-inflammatory factors in the mouse colon mucosa. The aim of this study was to determine the signaling pathways that mediate the transcriptional activation of pro-inflammatory cytokines in colon cancer epithelial cells treated with sulindac sulfide.We found that sulindac sulfide increased NF-κB signaling in HCT-15, HCT116, SW480 and SW620 cells, although the level of induction varied between cell lines. The drug caused a decrease in IκBα levels and an increase of p65(RelA) binding to the NF-κB DNA response element. It induced expression of IL-8, ICAM1 and A20, which was inhibited by the NF-κB inhibitor PDTC. Sulindac sulfide also induced activation of the AP-1 transcription factor, which co-operated with NF-κB in up-regulating IL-8. Up-regulation of NF-κB genes was most prominent in conditions where only a subset of cells was undergoing apoptosis. In TNFα stimulated conditions the drug treatment inhibited phosphorylation on IκBα (Ser 32) which is consistent with previous studies and indicates that sulindac sulfide can inhibit TNFα-induced NF-κB activation. Sulindac-induced upregulation of NF-κB target genes occurred early in the proximal colon of mice given a diet containing sulindac for one week.This study shows for the first time that sulindac sulfide can induce pro-inflammatory NF-κB and AP-1 signaling as well as apoptosis in the same experimental conditions. Therefore, these results provide insights into the effect of sulindac on pro-inflammatory signaling pathways, as well as contribute to a better understanding of the mechanism of sulindac-induced gastrointestinal side effects.
Keywords: Pro-inflammatory cytokines; NF-kB; AP-1; IL-8; A20; colon epithelial cells
Rights: © Mladenova et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
RMID: 0030084028
DOI: 10.1186/1478-811X-11-73
Appears in Collections:Medicine publications

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