My primary goal is to develop into an independent investigator in the field of colon-cancer chemoprevention. My long-term research objectives are to elucidate the mechanisms by which ursodeoxycholic acid exerts anticarcinogenic effects with respect to colon cancer. We have demonstrated that supplemental dietary cholic acid promoted the development of azoxymethane-induced rat colonic tumors. In contrast, dietary ursodeoxycholic acid (UDCA) inhibited tumorigenesis and suppressed cholic acid-induced tumor promotion. To examine the mechanisms by which UDCA causes anticarcinogenic effects, preliminary studies in the proposal demonstrated that UDCA inhibited Cox-2 gene expression at both the mRNA and protein levels and decreased Cox-2 immunostaining in stromal cells within the ACF. Furthermore, HCA-7 cells derived from a human colon cancer, demonstrated up-regulation of Cox-2 in response to deoxycholic acid (DCA). DCA is the major metabolite of the primary bile acid cholic acid, and is a potent tumor promoting bile acid. In contrast, UDCA inhibited DCA-induced Cox-2 up-regulation in HCA-7 cells, further supporting our hypothesis that the chemopreventive actions of UDCA involve, at least in part, the ability of UDCA to inhibit Cox-2 expression in colon cancer. HCA-7 cells, therefore, manifest a similar response to UDCA with respect to Cox-2 inhibition as observed in the AOM model. These cells will, therefore, serve as an ideal in vitro model to dissect the molecular events involved in Cox-2 dysregulation in colonic carcinogenesis. They will also allow us to identify potential mechanisms by which UDCA acts to inhibit Cox-2 expression, and thereby suppress tumorigenesis. In our Specific aims we propose to elucidate the signal transduction pathways and regulatory components by which DCA up-regulates Cox-2, while UDCA suppresses this induction. The current project fits well into my long-term research objectives to evaluate the molecular targets of this chemopreventive bile acid. Our findings in this proposal will also likely identify potential blomarkers that we will validate in a future study involving human ACF.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
1R03CA097540-01
Application #
6548254
Study Section
Special Emphasis Panel (ZCA1-SRRB-3 (M1))
Program Officer
Perloff, Marjorie
Project Start
2002-09-01
Project End
2004-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
1
Fiscal Year
2002
Total Cost
$76,250
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
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Khare, Sharad; Mustafi, Reba; Cerda, Sonia et al. (2008) Ursodeoxycholic acid suppresses Cox-2 expression in colon cancer: roles of Ras, p38, and CCAAT/enhancer-binding protein. Nutr Cancer 60:389-400
Fichera, Alessandro; Little, Nathaniel; Jagadeeswaran, Sujatha et al. (2007) Epidermal growth factor receptor signaling is required for microadenoma formation in the mouse azoxymethane model of colonic carcinogenesis. Cancer Res 67:827-35
Khare, Sharad; Holgren, Cory; Samarel, Allen M (2006) Deoxycholic acid differentially regulates focal adhesion kinase phosphorylation: role of tyrosine phosphatase ShP2. Am J Physiol Gastrointest Liver Physiol 291:G1100-12
Khare, Sharad; Cerda, Sonia; Wali, Ramesh K et al. (2003) Ursodeoxycholic acid inhibits Ras mutations, wild-type Ras activation, and cyclooxygenase-2 expression in colon cancer. Cancer Res 63:3517-23