title: Persistent cyclooxygenase-2 inhibition downregulates NF-{kappa}B, resulting in chronic intestinal inflammation in the min/+ mouse model of colon tumorigenesis.
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 E(2) (PGE(2)) expression and adenomas in the intestine of Min/+ mice after treatment for several weeks, but prolonged treatment increases PGE(2) production, resulting in drug-resistant tumor formation and transforming growth factor beta (TGFbeta)-dependent intestinal fibrosis. In this study, we examined pathways that regulate COX-2 expression and suppress chronic intestinal inflammation. We show that NF-kappaB signaling was inhibited in the ileum of Min/+ mice receiving long-term treatment with celecoxib. This effect was associated with inhibition of TGFbeta-associated kinase-1 and IkappaB kinase alpha/beta 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 NH(2)-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-kappaB. In ileum subjected to long-term celecoxib treatment, we noted relatively higher expression of COX-2, vascular endothelial growth factor, and interleukin-1beta in Paneth cells, whereas NF-kappaB 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.
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Adelaide M
authors.initials: AM
authors.lastname: Carothers
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Davids
authors.forename: Beatrice C
authors.initials: BC
authors.lastname: Damas
authors.forename: Monica M
authors.initials: MM
authors.lastname: Bertagnolli
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis; D000068579:Celecoxib; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D003092:Colitis / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015536:Down-Regulation; D007082:Ileum / Q000098:blood supply / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000096:biosynthesis; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D018952:Antigens, CD34; D000068579:Celecoxib; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D053583:Interleukin-1beta; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D011720:Pyrazoles; D013449:Sulfonamides; D051193:Toll-Like Receptors; D000099151:MAP Kinase Kinase Kinase 7