Journal
NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL
Volume 60, Issue 3, Pages 389-400Publisher
LAWRENCE ERLBAUM ASSOC INC-TAYLOR & FRANCIS
DOI: 10.1080/01635580701883003
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Funding
- NCI NIH HHS [CA097540, CA036745, CA117472] Funding Source: Medline
- NHLBI NIH HHS [HL34328] Funding Source: Medline
- NIDDK NIH HHS [P30DK42086, DK59327] Funding Source: Medline
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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 P (C/EBP beta), a transcriptional regulator of Cox-2. In HCA-7 colon cancer cells, DCA activated Ras and increased C/EBP beta and Cox-2 by a mechanism requiring the mitogen-activated protein kinase p38. UDCA inhibited DCA-induced p38 activation and decreased C/EBPP and Cox-2 upregulation. Using transient transfections, UDCA inhibited Cox-2 promoter and C/EBP reporter activation by DCA. Transfection with dominant-negative N-17-Ras abolished DCA-induced p38 activation and C/EBP,6 and Cox-2 upregulation. Taken together, these studies have identified a transcriptional pathway regulating Cox-2 expression involving Ras, p38, and C/EBP beta that is inhibited by UDCA. These signal transducers are novel targets of UDCA's chemopreventive actions.
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