This postdoctoral training proposal evaluates the hypothesis that expression of 15-Lipoxygenase (15-Lox) mediates the differentiation of colorectal cancer cells, via the activation of peroxisome proliferator activated receptors (PPAR) gamma and alpha. Experiments will utilize the Caco-2 colon carcinoma cell line, in which 15-Lox is highly upregulated during spontaneous differentiation. Interestingly, a function for 15-Lox products in Caco-2 differentiation has yet to be established. Experiments will specifically address the contribution of the 15-Lox products, 15-HETE and 15-HETE-G in promoting the differentiation of Caco-2 cells into enterocytes. 15-HETE and 15-HETE-G have previously been demonstrated to activate PPARgamma and PPARalpha, respectively, transcription factors with established roles in growth-arrest and differentiation in a number of cell types. Therefore, experiments will further explore the contribution of 15-Lox activity, and 15-HETE and 15-HETE-G production in PPAR activation. The roles of individual PPARs in the differentiation process will also be examined. This research will be the first test for a biological role of 15-HETE-G. In addition, it will evaluate the role of 15-Lox and PPARs in promoting growth arrest in colorectal cancer, providing novel insight into the mechanisms of cancer biology.
