This renewal application will propose experiments that extend previous studies from this laboratory demonstrating an enhancement of 12-0-tetradecanoylphorbol-13-acetate- (TPA) induced skin cancer promotion in mice fed high fat diet. These investigations used the two-stage model of skin carcinogenesis in which SENCAR mice initiated with 7,12-dimethylbenz(a)anthracene (DMBA) were fed the high fat diet in amounts equivalent to the calories consumed by the control group. We also determined that restriction of the diet to 60% of that consumed by control mice resulted in considerable inhibition of skin carcinogenesis. Our studies on the influence of these dietary factors on protein kinase C (PKC) indicated the possibility that dietary factors may act through modulation of this important cellular receptor for TPA. Both high fat diet and high caloric intake resulted in elevated PKC activity in soluble and particulate fractions of epidermal cells. Further experiments on the influence of dietary fat on membrane lipid composition and phosphatidylinositol (PI) metabolism provide evidence that the influence of dietary fat on PKC could result from effects on membrane lipids. Studies proposed in this renewal application will determine the influence of dietary fat and calorie intake in interaction with TPA on PKC activity and PKC isozyme profiles in basal epidermal cells. The influence of diet on membrane PI pools and turnover and on the activities of phospholipid modifying enzymes (phospholipase C and A2) will be explored. We will also attempt modification of membrane phospholipid composition in vitro for parallel studies. Interactions between fat and calories on tumorigenesis PKC and phospholipid metabolism will be assessed. Dietary fat and calorie effects on TPA induced proliferation in epidermal cells will be studied. Finally, dietary effects on early and late stages of promotion in mouse skin, including studies on the influence of dietary modification on the recruitment of initiated cells during the early stages of tumor promotion will be conducted. The experiments proposed in this application will expand our understanding of the mechanism(s) by which dietary fats influence skin tumor promotion and the relationship between fat and calorie effects. Since dietary fat acts at such a wide variety of sites it is likely that mechanisms identified in mouse skin may operate at other sites as well.
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