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 β (C/EBPβ), a transcriptional regulator of Cox-2. In HCA-7 colon cancer cells, DCA activated Ras and increased C/EBPβ and Cox-2 by a mechanism requiring the mitogen-activated protein kinase p38. UDCA inhibited DCA-induced p38 activation and decreased C/EBPβ and Cox-2 upregulation. Using transient transfections, UDCA inhibited Cox-2 promoter and C/EBP reporter activation by DCA. Transfection with dominant-negative ¹⁷N-Ras abolished DCA-induced p38 activation and C/EBPβ and Cox-2 upregulation. Taken together, these studies have identified a transcriptional pathway regulating Cox-2 expression involving Ras, p38, and C/EBPβ that is inhibited by UDCA. These signal transducers are novel targets of UDCA's chemopreventive actions.

ACKNOWLEDGMENTS

These studies were funded in part by the following grants: P30DK42086 [Digestive Diseases Research Core Center], CA036745 (M. Bissonnette), HL34328 (A. Samarel), CA097540 VA Merit Award (S. Khare), CA117472, and DK59327 (Y. C. Li) as well as by the Samuel Freedman Research Laboratories for Gastrointestinal Cancer Research. Additional funding was provided by the Department of Pathology Research Core Facilities of the University of Chicago and Cardiovascular Institute of the Loyola University.