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 ?-6 fatty acids are implicated in cancer due to the formation of deleterious metabolites from cyclooxygenase (COX)- catalyzed peroxidation. In contrast, ?-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 ?-6 that possesses beneficial bioactivities similar to ?-3s. However, the molecular mechanisms by which ?-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 ?-6 conversion and COX-catalyzed free radical peroxidation for use in dietary regimens to optimize cancer therapies in colon cancer treatment.
This proposal supports translational efforts to use modified ?-6 fatty acid diet supplements and COX-mediated free radical peroxidation to enhance the efficacies of chemo- and/or targeted therapy in colon cancer treatment. It addresses the fundamental but poorly understood question of how ?-6s (a more pervasive diet resource than ?-3s) could be appropriately used to sensitize cancer cell response to the chemo-drug 5-Fluorouracil and/or targeted therapeutic drug regorafenib in vitro and in vivo. The outcome of this translational study will guide us to optimize the effectiveness of colon cancer therapies and assure safer outcomes for cancer patients.
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