There are cogent data indicating a protective effect of n-3 polyunsaturated fatty acids (PUFA) e.g., eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on colon cancer. In contrast, dietary lipids rich in n-6 PUFA, e.g., linoleic acid (LA) and arachidonic acid (AA), enhance the development of colon tumors. This is significant because the typical Western diet contains 10 to 20 times more n-6 than n-3 PUFA. Unfortunately, to date, a unifying mechanistic hypothesis addressing why n-3 PUFA selectively suppress colon cancer compared to n-6 PUFA (the major dietary form of PUFA in the U.S. diet) is lacking. In the current funding period, we demonstrated that (i) dietary n-3 PUFA induce perturbations in colonocyte membrane microdomain (caveolae) lipid composition, suppressing oncogenic signaling and Ras protein trafficking;(ii) n-3 PUFA supplant arachidonic acid (AA) in colonocyte membrane phospholipids, with EPA in particular being metabolized into a novel 3-series E-prostaglandin (PGE3), a putative antitumorigenic-cyclooxygenase (COX) metabolite;and (iii) the proapoptotic- chemoprotective effect of n-3 PUFA is enhanced when a highly fermentable fiber, pectin (or its fermentation product-butyrate) is added to the diet. We postulate that the failure to address an interaction between dietary fat and fiber may explain why the chemoprotective effects of fiber are obscured in prospective cohort studies. Therefore, the overall goal of this proposal is to further elucidate how dietary n-3 PUFA and fermentable fiber up-regulate apoptosis effector mechanisms in colonocytes, thereby reducing colon cancer risk. An array of experimental models will be used, including in vivo (azoxymethane-injected oxidatively stressed SOD2+/-, Gpx4+/- knock outs, Gpx4Tg and fat-1 transgenic mouse models) and in vitro (normal and malignant transformed mouse and human colonocyte cell lines) in order to test our primary hypothesis that n-3 PUFA and butyrate work in a coordinated manner to potentiate mitochondrial-mediated apoptosis. As a complementary hypothesis, we propose that DHA and possibly EPA alter colonocyte membrane lipid microdomain composition, thereby favorably modulating eicosanoid metabolism and the relay of extracellular signals from surface receptors to downstream signaling networks. The following specific aims are proposed:
Aim #1 will determine the mechanisms by which n-3 PUFA and butyrate interaction modulate intrinsic (mitochondria-mediated) cell death signaling in the colon;
Aim #2 will determine the mechanisms by which n-3 PUFA alter the spatio-temporal segregation of Ras-dependent signals;
and Aim #3 will characterize the putative chemoprotective properties of a novel EPA-derived cyclooxygenase product, PGE3. The consumption of EPA and DHA may prove an effective adjuvant therapy in colon cancer. Therefore, it is both appropriate and timely to determine precisely how n-3 PUFA modulate cell signaling networks and reduce colon cancer risk.A growing body of literature supports the contention that bioactive food components containing n-3 polyunsaturated fatty acids (PUFA) are important in suppressing colon cancer. Consistent with the objectives and scope of PA-07-100, Prioritizing molecular targets for cancer prevention with nutritional combinations , the overall goal of this proposal is to elucidate how dietary n-3 PUFA and fermentable fiber up-regulate apoptosis effector mechanisms in colonocytes, thereby reducing colon cancer risk.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA059034-18
Application #
8212304
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Emenaker, Nancy J
Project Start
1994-12-23
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
18
Fiscal Year
2012
Total Cost
$256,131
Indirect Cost
$78,031
Name
Texas A&M University
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
078592789
City
College Station
State
TX
Country
United States
Zip Code
77845
Monk, Jennifer M; Turk, Harmony F; Fan, Yang-Yi et al. (2014) Antagonizing arachidonic acid-derived eicosanoids reduces inflammatory Th17 and Th1 cell-mediated inflammation and colitis severity. Mediators Inflamm 2014:917149
Cho, Youngmi; Turner, Nancy D; Davidson, Laurie A et al. (2014) Colon cancer cell apoptosis is induced by combined exposure to the n-3 fatty acid docosahexaenoic acid and butyrate through promoter methylation. Exp Biol Med (Maywood) 239:302-10
Turk, Harmony F; Monk, Jennifer M; Fan, Yang-Yi et al. (2013) Inhibitory effects of omega-3 fatty acids on injury-induced epidermal growth factor receptor transactivation contribute to delayed wound healing. Am J Physiol Cell Physiol 304:C905-17
Turk, Harmony F; Chapkin, Robert S (2013) Membrane lipid raft organization is uniquely modified by n-3 polyunsaturated fatty acids. Prostaglandins Leukot Essent Fatty Acids 88:43-7
Hou, Tim Y; Monk, Jennifer M; Fan, Yang-Yi et al. (2012) n-3 polyunsaturated fatty acids suppress phosphatidylinositol 4,5-bisphosphate-dependent actin remodelling during CD4+ T-cell activation. Biochem J 443:27-37
Saldua, Meagan A; Olsovsky, Cory A; Callaway, Evelyn S et al. (2012) Imaging inflammation in mouse colon using a rapid stage-scanning confocal fluorescence microscope. J Biomed Opt 17:016006
Monk, Jennifer M; Kim, Wooki; Callaway, Evelyn et al. (2012) Immunomodulatory action of dietary fish oil and targeted deletion of intestinal epithelial cell PPARýý in inflammation-induced colon carcinogenesis. Am J Physiol Gastrointest Liver Physiol 302:G153-67
Kolar, Satya; Barhoumi, Rola; Jones, Chris K et al. (2011) Interactive effects of fatty acid and butyrate-induced mitochondrial Ca²? loading and apoptosis in colonocytes. Cancer 117:5294-303
Kachroo, Priyanka; Ivanov, Ivan; Davidson, Laurie A et al. (2011) Classification of diet-modulated gene signatures at the colon cancer initiation and progression stages. Dig Dis Sci 56:2595-604
Fan, Yang-Yi; Ran, Qitao; Toyokuni, Shinya et al. (2011) Dietary fish oil promotes colonic apoptosis and mitochondrial proton leak in oxidatively stressed mice. Cancer Prev Res (Phila) 4:1267-74

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