NDLI: Persistent Cox-2 inhibition downregulates NF-κB resulting in chronic intestinal inflammation in the Min/+ mouse model of colon tumorigenesis

Content Provider	PubMed Central
Author	Carothers, Adelaide M. Davids, Jennifer S. Damas, Beatrice C. Bertagnolli, Monica M.
Abstract	COX-2 inhibition prevents adenoma formation in humans and mouse models of colon cancer. The selective COX-2 inhibitor, celecoxib, reduces COX-2 and PGE2 expression and adenomas in the intestine of Min/+ mice after treatment for several weeks, but prolonged treatment increases PGE2 production, resulting in drug-resistant tumor formation and TGFβ-dependent intestinal fibrosis. In this study, we examined pathways that regulate COX-2 expression and suppress chronic intestinal inflammation. We show that NF-κB signaling was inhibited in the ileum of Min/+ mice receiving long-term treatment with celecoxib. This effect was associated with inhibition of TAK-1 and IKKα/β activities and reduced expression of the Toll-like receptors TLR2 and TLR4 that enhance colonic barrier function. Additionally, we observed reduced activities of protein kinases JNK1 and PKA and transcription factor CREB, regulators of COX-2 expression which crosstalk with NF-κB. In ileum subjected to long-term celecoxib treatment, we noted relatively higher expression of COX-2, VEGF, and IL-1β in Paneth cells, while NF-κB and COX-2 were more strongly expressed by an expanded population of stromal myofibroblasts. Our findings argue that celecoxib resistance is an acquired adaptation to changes in the crypt microenvironment that is associated with chronic intestinal inflammation and impaired acute wound-healing responsiveness.
Related Links	http://dx.doi.org/10.1158/0008-5472.can-09-4289
Ending Page	4442
Page Count	10
Starting Page	4433
File Format	PDF
ISSN	00085472
e-ISSN	15387445
Journal	Cancer research
Issue Number	11
Volume Number	70
Language	English
Publisher Date	2010-06-01
Access Restriction	Open
Subject Keyword	Cancer Research Oncology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology

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