New Paradigm of Targeting COX-Catalyzed Free Radical Peroxidation in Colon Cancer

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 DESCRIPTION (provided by applicant): Colon cancer remains a significant health concern as the third most prevalent cancer and the second leading cause of cancer deaths in the United States. Research suggests that ω-6 fatty acids are implicated in cancer due to the formation of deleterious metabolites from cyclooxygenase (COX)- catalyzed peroxidation. In contrast, ω-3 fatty acid-based dietary care has been applied in colon cancer treatment along with a variety of therapeutic approaches. Increasing evidence indicates that dihomo-- linolenic acid (DGLA) may represent an exceptional ω-6 that possesses beneficial bioactivities similar to ω-3s. However, the molecular mechanisms by which ω-6s can influence human health are still unclear. Our preliminary data has shown for the first time that, via COX-catalyzed peroxidation, DGLA produces exclusive free radicals that inhibit colon cancer cell growth, while its downstream product arachidonic acid (the conversion mediated by 5-desaturase) produces endoperoxide-derived free radicals that may stimulate cancer cell growth. We hypothesize that (1) the distinct free radical byproducts formed from COX-catalyzed peroxidation of arachidonic acid vs. DGLA account for their opposing bioactivities, and (2) down-regulation of 5-desaturase can inhibit colon cancer cell growth and enhance cancer therapy by limiting the conversion of DGLA to arachidonic acid, activating DGLA mediated pro-apoptotic and anti-proliferative pathways. Two specific aims will be pursued: (AIM-1) determine the role in colon cancer cell growth of the distinct arachidonic acid and DGLA free radical byproducts formed from COX-catalyzed peroxidation. We will test the hypothesis that the distinct free radical byproducts of arachidonic acid and DGLA are growth stimulatory and inhibitory, respectively, to colon cancer cells (HCA-7, HT-29, and HCT-116, with 3 different COX-2 and p53 statuses). These byproducts will be studied for their individual and combined effects on the expression of key proteins involved in the cell cycle and the apoptotic response; and (AIM-2) determine whether down-regulation of 5-desaturase enhances the formation of DGLA free radical byproducts during COX-catalyzed peroxidation, leading to inhibition of colon cancer growth and enhanced responses to chemo- and/or targeted therapeutic drugs in vitro and in vivo. We will use in vitro (three colon cancer cell lines and their 5-desaturase knockdown counterparts) and in vivo (xenograft tumors manipulated with 5- desaturase shRNA) strategies to test the hypothesis that down-regulation of 5-desaturase will intensify DGLA peroxidation catalyzed by COX-2 (high and readily inducible in cancer), enhance the inhibition of growth, and improve the efficacy of chemo- and/or targeted therapy. Our long term objective is to develop a strategy to modify cellular ω-6 conversion and COX-catalyzed free radical peroxidation for use in dietary regimens to optimize cancer therapies in colon cancer treatment.