COLONIC CYTOKINETICS AND CELL SIGNALING--DIETARY EFFECT

在饮食因素中，有很强的流行病学、临床和

Among dietary factors, there is strong epidemiological, clinical and experimental data indicating a protective effect on n-3 polyunsaturated fatty acids (n-3 PUFAs; eicosapentaenoic acid, 20:5n- 3 and docosahexaenoic acid, 22:n-3) on colon cancer. We have recently demonstrated that dietary n-3 PUFAs confer protection against experimental carcinogenesis, i.e., a reduction in tumor incidence, in part by enhancing the deletion of cells through activation of apoptosis, which may reduce the accumulation of genetic errors. These data support our postulate that dietary n-3 PUFAs act as anticarcinogens by facilitating the apoptotic removal of carcinogen adducted cells. In order to further elucidate the mechanism(s) by which n-3 PUFAs-induce apoptosis. We will utilize the highly relevant rat model of colon carcinogenesis to determine whether n-3 PUFAs modulate DNA adduct formation, removal (DNA repair) and/or deletion (apoptosis) during the initial stages of malignant transformation. We have also recently show that n-3 PUFAs prevent the carcinogen-induced chronic down-regulation of colonic protein kinase C (PKC) delta (novel), zeta (atypical), and the selective up- regulation of PKC betaII (classical). This is significant because the maintenance of crypt PKC levels may sustain the homeostatic balance between cell proliferation and apoptosis. Therefore, we have hypothesized that n-3 PUFAs reduce colon cancer incidence in part by blocking the effects of carcinogen on colonic PKC isozyme-related signal transduction. To further determine the significance of n-3 PUFA-induced changes in colonic PKC expression, we will elucidate the role of specific PKC isozymes in colon tumor development by using a targeted pharmacological inhibitor in vivo in combination with overepression and antisense strategies in vitro. Elucidation of the mechanism(s) by which dietary n-3 PUFAs reduce colon cancer incidence will lead to the establishment of dietary guidelines designed to reduce colon cancer morbidity and mortality. This experimental approach is particularly relevant because despite advancement in the treatment of colon cancer, the 5 year mortality rate has not appreciable improved over the past 4 decades. Therefore, chemopreventive dietary strategies must be developed in order to decrease the risk of colon cancer.