Colon Carcinogenesis through Fat-induced Oxidative Stress

Epidemiological studies demonstrate a clear correlation beween fat-rich nutrition and colon carcinogenesis. Among European countries Austria has one of the highest incidence and mortality rates of colon cancer. Based on the present scientific knowledge we developed the hypothesis that under the influence of fat-rich diet an oxidative damage of colon epithelial cells occurs which initiates or at least promotes the malignant transformation to cancer cells. In the predecessing project (Nr. P 12807 MED) we were able to corroborate the first part of our working hypothesis. Oils and dietary fats while in contact with other nutritional compounds, are forming highly active oxidants which attack biological membranes oxidatively. Furthermore we have shown that oxidatively modified cell membranes lead to alterations of cell growth and cell division, in a way that has already been observed in carcinogenic cell transformation. The second project will therefore deal with the basis of cell regulation of influence:of cell growth, cell division and transformation to carcinoma cells which are triggered by this oxidative influence. Aim of this experimental analysis is the development of preventive strategies that reduce the risk of colon cancer and furthermore the risk of other nutrition-linked cancer forms. For this purpose the content of potential prooxidants of different oils and frying fats will be analyzed. A special focus of interest will be the content of polyunsaturated fatty acids and lipid hydroperoxides formed as a consequence of storage and heating. As has already been shown in the preceding project, these compounds, in combination with other natural nutritional constituents are responsible for the oxidative attack on colon epithelial cells. Exposition of colon cell cultures to the prooxidative nutrition cocktail is designed in order to investigate geno- and cytotoxic metabolites such as hydroxynonenal (HNE) and their impact on cell growth and cell division. In detail we will investigat the formation of promutagenic HNE-etheno DNA adducts, the influence on the rate of apoptosis as well as intracellular signal transduction. The efficiency of endogenously upregulated protection mechanisms (expression of selenium-dependent glutatione peroxidase) as well as exogenous antioxidants as food additives will be analyzed according to the previously analyzed markers of oxidative cell transformation.