Ursodeoxycholic acid suppresses Cox-2 expression in colon cancer: roles of Ras, p38, and CCAAT/enhancer-binding protein.
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.
Khare
Sharad
S
Department of Medicine, Loyola University Medical Center, Maywood, Illinois 60153, USA. skhare@lumc.edu
Mustafi
Reba
R
Cerda
Sonia
S
Yuan
Weihua
W
Jagadeeswaran
Sujatha
S
Dougherty
Urszula
U
Tretiakova
Maria
M
Samarel
Allen
A
Cohen
Greg
G
Wang
Julia
J
Moore
Christopher
C
Wali
Ramesh
R
Holgren
Cory
C
Joseph
Loren
L
Fichera
Alessandro
A
Li
Yan Chun
YC
Bissonnette
Marc
M
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*
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