title: Ursodeoxycholic acid suppresses Cox-2 expression in colon cancer: roles of Ras, p38, and CCAAT/enhancer-binding protein.
abstract: In the azoxymethane (AOM) model of experimental rodent colon cancer, cholic acid and its colonic metabolite deoxycholic acid (DCA) strongly promote tumorigenesis. In contrast, we showed that ursodeoxycholic acid (UDCA), a low abundance bile acid, inhibited AOM tumorigenesis. Dietary UDCA also blocked the development of tumors with activated Ras and suppressed cyclooxygenase-2 (Cox-2) upregulation in AOM tumors. In this study, we compared the effect of dietary supplementation with tumor-promoting cholic acid to chemopreventive UDCA on Cox-2 expression in AOM tumors. Cholic acid enhanced Cox-2 upregulation in AOM tumors, whereas UDCA inhibited this increase and concomitantly decreased CCAAT/enhancer binding protein beta (C/EBPbeta), a transcriptional regulator of Cox-2. In HCA-7 colon cancer cells, DCA activated Ras and increased C/EBPbeta and Cox-2 by a mechanism requiring the mitogen-activated protein kinase p38. UDCA inhibited DCA-induced p38 activation and decreased C/EBPbeta and Cox-2 upregulation. Using transient transfections, UDCA inhibited Cox-2 promoter and C/EBP reporter activation by DCA. Transfection with dominant-negative (17)N-Ras abolished DCA-induced p38 activation and C/EBPbeta and Cox-2 upregulation. Taken together, these studies have identified a transcriptional pathway regulating Cox-2 expression involving Ras, p38, and C/EBPbeta that is inhibited by UDCA. These signal transducers are novel targets of UDCA's chemopreventive actions.
authors.affiliation: Department of Medicine, Loyola University Medical Center, Maywood, Illinois 60153, USA. skhare@lumc.edu
authors.forename: Sharad
authors.initials: S
authors.lastname: Khare
authors.forename: Reba
authors.initials: R
authors.lastname: Mustafi
authors.forename: Sonia
authors.initials: S
authors.lastname: Cerda
authors.forename: Weihua
authors.initials: W
authors.lastname: Yuan
authors.forename: Sujatha
authors.initials: S
authors.lastname: Jagadeeswaran
authors.forename: Urszula
authors.initials: U
authors.lastname: Dougherty
authors.forename: Maria
authors.initials: M
authors.lastname: Tretiakova
authors.forename: Allen
authors.initials: A
authors.lastname: Samarel
authors.forename: Greg
authors.initials: G
authors.lastname: Cohen
authors.forename: Julia
authors.initials: J
authors.lastname: Wang
authors.forename: Christopher
authors.initials: C
authors.lastname: Moore
authors.forename: Ramesh
authors.initials: R
authors.lastname: Wali
authors.forename: Cory
authors.initials: C
authors.lastname: Holgren
authors.forename: Loren
authors.initials: L
authors.lastname: Joseph
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fichera
authors.forename: Yan Chun
authors.initials: YC
authors.lastname: Li
authors.forename: Marc
authors.initials: M
authors.lastname: Bissonnette
mesh_terms: D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D002478:Cells, Cultured; D018890:Chemoprevention; D019826:Cholic Acid / Q000633:toxicity; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000201:enzymology*; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D019587:Dietary Supplements; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D011905:Genes, ras / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D052246:Cyclooxygenase 2 Inhibitors; D014157:Transcription Factors; D014580:Ursodeoxycholic Acid; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases; D019826:Cholic Acid; D001397:Azoxymethane