Ulcerative colitis is the single major risk factor for the development of colitis-associated colon cancer (CAC). Lifetime risk accruals for CAC may be as high as 43%, and CAC accounts for 1 in 6 deaths due to inflammatory bowel diseases. There is no known non-surgical chemopreventive strategy for CAC, although there is compelling evidence that diets that are rich in n-3 polyunsaturated fatty acids (n-3 PUFA, also known as (3 PUFA) suppress both colonic inflammation and carcinogen-induced colon cancer. These observations suggest that diets that are rich in n-3 PUFA may be effective means to prevent progression from inflammation to colon cancer, and one of our objectives is to test this hypothesis in a newly developed animal model of CAC. Our working hypothesis holds that the chemopreventive effects of n-3 PUFA are mediated, at least in part, by two lipid receptors: protein kinase C-beta II (PKC(ll) and peroxisome proliferator-activated receptor-gamma (PPAR(). Both of these entities have been shown to be important in the etiology of sporadic colon cancer, but their role in dietary lipid signaling in the colon has not been defined, and their role in CAC has not been investigated. We will utilize genetic knockout mice to determine if the tumor-suppressive effects of n-3 PUFA are dependent upon the expression of PKCpll or PPAR( in the colonic epithelium. Completion of these experiments will provide pre-clinical proof-of-principle for the use of dietary lipids in chemoprevention of CAC and will define the biologically plausible mechanisms that may account for alteration of CAC risk by essential dietary lipids. Confirmation of our hypotheses will provide essential pre-clinical proof-of-principle in support of clinical trials to determine if dietary n-3 PUFA prevents progression from colonic inflammation to CAC, will identify the role of PKC(ll and PPAR( in CAC, and may ultimately provide an alternative means of chemoprevention to patients who presently have no alternative to colectomy. ? ? ?
| Su, Weidong; Necela, Brian M; Fujiwara, Kosaku et al. (2008) The high affinity peroxisome proliferator-activated receptor-gamma agonist RS5444 inhibits both initiation and progression of colon tumors in azoxymethane-treated mice. Int J Cancer 123:991-7 |
| Su, Weidong; Bush, Craig R; Necela, Brian M et al. (2007) Differential expression, distribution, and function of PPAR-gamma in the proximal and distal colon. Physiol Genomics 30:342-53 |
| Bush, Craig R; Havens, Jennifer M; Necela, Brian M et al. (2007) Functional genomic analysis reveals cross-talk between peroxisome proliferator-activated receptor gamma and calcium signaling in human colorectal cancer cells. J Biol Chem 282:23387-401 |
| Chen, Lu; Necela, Brian M; Su, Weidong et al. (2006) Peroxisome proliferator-activated receptor gamma promotes epithelial to mesenchymal transformation by Rho GTPase-dependent activation of ERK1/2. J Biol Chem 281:24575-87 |
