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• W2172015504 abstract "Abstract Cyclooxygenase-2 (COX-2) inhibition prevents adenoma formation in humans and mouse models of colon cancer. The selective COX-2 inhibitor celecoxib reduces COX-2 and prostaglandin E2 (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 transforming growth factor β (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 TGFβ-associated kinase-1 and IκB kinase α/β activities and reduced expression of the Toll-like receptor (TLR) 2 and TLR4 that enhance colonic barrier function. Additionally, we observed reduced activities of protein kinases c-Jun NH2-terminal kinase 1 and protein kinase A and transcription factor cyclic AMP–responsive element binding protein, regulators of COX-2 expression, which cross-talk with NF-κB. In ileum subjected to long-term celecoxib treatment, we noted relatively higher expression of COX-2, vascular endothelial growth factor, and interleukin-1β in Paneth cells, whereas 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. Cancer Res; 70(11); 4433–42. ©2010 AACR." @default.
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• W2172015504 date "2010-06-01" @default.
• W2172015504 modified "2023-10-03" @default.
• W2172015504 title "Persistent Cyclooxygenase-2 Inhibition Downregulates NF-κB, Resulting in Chronic Intestinal Inflammation in the Min/+ Mouse Model of Colon Tumorigenesis" @default.
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• W2172015504 doi "https://doi.org/10.1158/0008-5472.can-09-4289" @default.
• W2172015504 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3242378" @default.
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