Fatty acid desaturase activity, fish oil and colorectal cancer chemoprevention

Summary

Principal Investigator: Harvey J Murff
Abstract: DESCRIPTION (provided by applicant): Colorectal cancer is the second leading cause of cancer-related mortality within the United States. Animal models and observational studies have suggested that marine-derived n-3 polyunsaturated fatty acids [PUFA] such as eicosapentanoic acid [EPA] and docosahexanoic acid [DHA] may reduce the risk of colorectal cancer. In addition, it may be the relative proportion of n-3 to n-6 PUFAs that best determines the chemopreventive effects of fish oils. This ratio is important because the n-6 PUFA, arachidonic acid (ARA), is converted via the cyclo-oxygenase pathway to prostaglandin E2 (PGE2), an inflammatory eicosanoid aberrantly produced in colorectal neoplasms while EPA is converted to the anti-inflammatory prostaglandin E3 (PGE3). While the ratio of n-6 to n-3 PUFAs can be manipulated through dietary measures, genetic factors may also influence this ratio. Recent genome-wide association and haplotype studies have demonstrated that up to 28% of the additive variance in tissue levels of ARA is explained by variants in a single gene, fatty acid desaturase 1 (FADS1). FADS1 is the rate-limiting enzyme in the conversion of linoleic acid, the most commonly consumed PUFA, to ARA, and homozygotes for the T allele (population frequency of 13%, HapMap -CEU) in rs174537 have lower fatty acid desaturase activity and subsequently lower tissue levels of ARA. Our hypothesis is that individuals with genetically determined lower activity of FADS1 will derive greater benefit from fish oil supplementation than individuals with higher FADS1 activity because of lower tissue levels of ARA and subsequently a more favorable n-6 to n-3 PUFA ratio. To test this hypothesis we will recruit 150 participants with recently identified adenomatous polyps and conduct a 6-month double blind 3 X 2 factorial randomized controlled trial. Our first factor will be FADS1 genotype (GG, GT, and TT) and our second factor will be fish oil supplementation (fish oil versus placebo). Our primary outcome will be the change in rectal epithelial cell proliferation as measured by Ki-67 labeling and rectal crypt apoptosis as measured by TUNEL. Secondary endpoints will include rectal epithelial cell expression of COX-2 and 15-PGDH, rectal cell production of PGE2 and PGE3, rectal mucosal tissue levels of fatty acids, and changes in biomarkers of inflammation (C-reactive protein), adipokines (leptin, adiponectin), and markers of insulin sensitivity. Our specific aims include: 1) to determine the efficacy of fish oil supplements on rectal epithelial cell proliferation indexes and markers of rectal crypt apoptosis, and 2) to determine the effect of genetically-determined fatty acid desaturase 1 activity on fish oil supplementation for colorectal cancer chemoprevention. Our long-term objectives are to determine genetic factors that might influence the efficacy of fish oil supplementation in order to conduct a more definitive adenoma recurrence trial using marine-derived n-3 PUFAs. We anticipate that fish oil will have anti-neoplastic effect and individuals with low FADS1 activity will have a greater response compared to individuals with high FADS1 activity.
Funding Period: 2011-09-15 - 2015-07-31
more information: NIH RePORT

Top Publications

  1. pmc Dietary intake of PUFAs and colorectal polyp risk
    Harvey J Murff
    Division of General Internal Medicine, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
    Am J Clin Nutr 95:703-12. 2012

Detail Information

Publications1

  1. pmc Dietary intake of PUFAs and colorectal polyp risk
    Harvey J Murff
    Division of General Internal Medicine, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
    Am J Clin Nutr 95:703-12. 2012
    ..Marine-derived n-3 (omega-3) PUFAs may reduce risk of developing colorectal cancer; however, few studies have investigated the association of n-3 PUFA intakes on colorectal polyp risk...

Research Grants62

  1. Omega-3 Fatty Acid Effects on Pancreatitis and Adenocarcinoma Development
    Christopher A Jolly; Fiscal Year: 2013
    ..This data may show an important role for the omega-3 PUFAs, especially EPA, in cancer prevention because they are well known anti-inflammatory agents and are widely consumed by people in the United States. ..
  2. Biology &Transplantation of the Human Stem Cell
    John E Wagner; Fiscal Year: 2013
    ..abstract_text> ..
  3. ASPIRIN/FOLATE PREVENTION OF LARGE BOWEL POLYPS
    JOHN ANTHONY BARON; Fiscal Year: 2013
    ..We will also explore whether aspirin-triggered lipoxins - recently identified anti-inflammatory eicosanoids - played a role in the chemopreventive effects of aspirin. ..
  4. The Comprehensive Center for Chemical Probe Discovery and Optimization at Scripps
    Hugh Rosen; Fiscal Year: 2013
    ..and high content analysis (HCA) are utilized for screening efforts. More information can be found at: http://hts.florida.scripps.edu/ ..
  5. Inflammation and Colorectal Neoplasia
    Andrew T Chan; Fiscal Year: 2013
    ..S., its optimal use in light of its toxicities remains uncertain. We will investigate the role of inflammation in colorectal carcinogenesis to define predictors of susceptibility for tailored preventative strategies. ..
  6. Role of Eicosanoids in Renal Function
    NANCY JOAN BROWN; Fiscal Year: 2013
    ..These are needed for the development of meaningful approaches for: a) the unequivocal definition of human pathophysiological significance, and b) future pharmacological targeting, and clinical diagnosis and intervention. ..
  7. M.D. Anderson Gynecologic SPORE for Uterine Cancers
    KAREN HSIEH LU; Fiscal Year: 2013
    ..Four Cores will support these projects. Core A (Administrative Core), Core B (Pathology Core), Core C Biomarkers Core, and Core D (Biostatistics and Bioinformatics Core). ..
  8. Program Project: Growth, Differentiation and Disease of Urothelium
    Tung Tien Sun; Fiscal Year: 2013
    ..abstract_text> ..
  9. Selenium Colorectal Cancer Chemoprevention Trials
    PATRICIA ANN THOMPSON; Fiscal Year: 2013
    ..In secondary analyses, we will investigate whether or not baseline Se levels, genetic background, and/or use of low-dose aspirin modify Se effects on CRA occurrence or risk for T2D. ..
  10. NEW MODALITIES FOR TREATMENT OF PAIN AND DRUG ABUSE
    Victor J Hruby; Fiscal Year: 2013
    ....
  11. Mechanisms of tumor suppressor gene reactivation in colon cancer by berries
    Li Shu Wang; Fiscal Year: 2013
    ..We now propose to evaluate the anthocyanins in berries for their ability to demethylate and reactivate tumor suppressor genes in colon cancer. ..
  12. Colorectal Cancer Prevention Through Thyroid Hormone Targets
    ADAM ROBERT BROWN; Fiscal Year: 2013
    ..The successful completion of the study will provide insight into potential age-dependent targets that may lead to the development of new therapies to prevent or treat age-related colorectal cancer. ..
  13. Colorectal Chemoprevention with Calcium and Vitamin D
    JOHN ANTHONY BARON; Fiscal Year: 2013
    ....
  14. Functional Analysis of Cyclooxygenase-2
    Lawrence J Marnett; Fiscal Year: 2013
    ..These substrate-selective inhibitors may represent candidate cancer chemopreventive agents that lack the gastrointestinal and cardiovascular side effects of currently marketed NSAIDs. ..
  15. Ether Lipids, Elcosanoids, and Lung Cell Pathophysiology
    CHRISTINA CARROLL LESLIE; Fiscal Year: 2013
    ..By using multidisciplinary approaches, we will determine the structural identity of lipid mediators, the molecular mechanisms involved in their production and how they function to regulate lung responses. ..
  16. Functional Consequences of Impaired Autophagy in Aging
    ANA M CUERVO; Fiscal Year: 2013
    ..Significance: These studies may ultimately lead to fundamental insights for understanding, treating or preventing the metabolic alterations and declined cognitive and immune function characteristic of elders. ..
  17. Novel Sulindac Derivatives for Colon Cancer Chemoprevention
    Robert C Reynolds; Fiscal Year: 2013
    ..This multidisciplinary research proposal may lead to a novel strategy for colon cancer chemoprevention. ..
  18. The Sphingolipid Pathway in Colon Cancer Chemoprevention
    Toshihiko Kawamori; Fiscal Year: 2013
    ..abstract_text> ..
  19. STUDY OF REG RECEPTOR-LIGAND BIOLOGY IN GI MUCOSA
    BRIAN KEITH DIECKGRAEFE; Fiscal Year: 2013
    ..These studies will provide critical insight into the potential role of Reg IV antagonists as a new treatment for gastrointestinal cancers. ..
  20. Endogenous Anti-Inflammatory Lipid Mediators, Fish Oil and Post-Operative Atrial
    Dariush Mozaffarian; Fiscal Year: 2013
    ..placebo, on these MEFAs response;and the relationship of MEFAs levels with POAF. ..
  21. Colon Cancer Chemoprevention and COX-2 Suppression by Ursodeoxycholic Acid
    Sharad Khare; Fiscal Year: 2013
    ..It will be useful in the development of better therapeutic interventions, as potential Cox-2 inhibitors are considered toxic for human use. ..
  22. A novel mouse prostate carcinogenesis model for dietary cancer prevention researc
    Chung S Yang; Fiscal Year: 2013
    ....
  23. Structural bases of the functions of RNA-protein machines
    THOMAS ARTHUR STEITZ; Fiscal Year: 2013
    ..Also of interest will be the ways in which the structures and properties of RNA molecules can be utilized to carry out various biological functions often analogous to those performed by proteins. ..
  24. Vaccine Immunotoxin and Radioimmunotherapy of Primary and Metastatic CNS Tumors
    Darell D Bigner; Fiscal Year: 2013
    ..abstract_text> ..
  25. Small Molecule Induction of 15-PGDH: A Target in Colon Cancer Chemoprevention
    JOHN JAMES LETTERIO; Fiscal Year: 2013
    ..The observations outlined above are the basis for our hypothesis that colon cancer chemoprevention by triterpenoids requires a TGF-b-dependent induction of 15- PGDH. ..
  26. Penn TREC Survivor Center
    Kathryn H Schmitz; Fiscal Year: 2013
    ..abstract_text> ..
  27. Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI)
    Thomas A Sellers; Fiscal Year: 2013
    ..g., mucinous and clear cell). ..
  28. Metabolic Actions of Omega-3 Fatty Acids on Inflammation
    Michael Miller; Fiscal Year: 2013
    ..Favorable outcomes from this study could translate into a new approach to improve heart disease risk in men and women with the metabolic syndrome. ..
  29. Comprehensive NeuroAIDS Core Center
    Kamel Khalili; Fiscal Year: 2013
    ..abstract_text> ..
  30. The Role of Bioactive Lipids in Inflammation and Cancer
    RAYMOND NELSON DUBOIS; Fiscal Year: 2013
    ..Information gained from these studies will be important for achieving the long-term goal of reducing the cancer burden and revealing more effective ways to prevent cancer. ..
  31. Chemopreventive effect of fish oil derived EPA in lung cancer
    Peiying Yang; Fiscal Year: 2013
    ..This proposal intends to define a novel targeted natural chemopreventive agent against lung cancer. ..
  32. Functional Annotation of the Pancreatic Cancer Genome
    Steven D Leach; Fiscal Year: 2013
    ..Together, these studies will dramatically accelerate the functional annotation of the pancreatic cancer genome, setting the stage for future therapeutic applications. ..
  33. Comparative Mechanisms of Cancer Chemoprevention
    Roderick H Dashwood; Fiscal Year: 2013
    ..This application is innovative and timely in bridging basic mechanisms, preclinical models, and human studies of epigenetics and diet. ..
  34. Type II 11B-Hydroxysteroid Dehydrogenase and Colorectal Tumorigenesis
    Mingzhi Zhang; Fiscal Year: 2013
    ..abstract_text> ..
  35. Personalized Prevention of Colorectal Cancer
    Chang Yu; Fiscal Year: 2013
    ....
  36. Mechanisms of CDX2 regulation of the IGF axis
    Duyen Dang; Fiscal Year: 2013
    ..This line of investigation provides the first insights into how CDX2 can function as both a cell growth promoter and suppressor. This approach would hopefully lead to novel clinical strategies for colon cancer prevention and therapy. ..