Intestinal homeostasis is precisely regulated by a number of endogenous regulatory molecules but significantly influenced by dietary compounds. Malfunction of this system may result in chronic inflammation and cancer. Dietary essential n-3 polyunsaturated fatty acids (PUFAs) and short-chain fatty acid butyrate produced from fibre display anti-inflammatory and anticancer activities. Both compounds were shown to modulate the production and activities of TNF family cytokines. Cytokines from the TNF family (TNF- α, TRAIL, and FasL) have potent inflammatory activities and can also regulate apoptosis, which plays an important role in cancer development. The results of our own research showed enhancement of apoptosis in colon cancer cells by a combination of either docosahexaenoic acid (DHA) or butyrate with TNF family cytokines, especially by promotion of the mitochondrial apoptotic pathway and modulation of NF κ B activity. This review is focused mainly on the interaction of dietary PUFAs and butyrate with these cytokines during colon inflammation and cancer development. We summarised recent knowledge about the cellular and molecular mechanisms involved in such effects and outcomes for intestinal cell behaviour and pathologies. Finally, the possible application for the prevention and therapy of colon inflammation and cancer is also outlined.

Department of Cytokinetics Institute of Biophysics Academy of Sciences of the Czech Republic v v i Královopolská 135 612 65 Brno Czech Republic

Department of Cytokinetics Institute of Biophysics Academy of Sciences of the Czech Republic v v i Královopolská 135 612 65 Brno Czech Republic ; Institute of Experimental Biology Department of Animal Physiology and Immunology Faculty of Science Masaryk University Kotlářská 2 611 37 Brno Czech Republic

Zobrazit více v PubMed

Bertrand FE, Angus CW, Partis WJ, Sigounas G. Developmental pathways in colon cancer: crosstalk between WNT, BMP, Hedgehog and Notch. Cell Cycle. 2012;11:4344–4351. PubMed PMC

Gunther C, Neumann H, Neurath MF, Becker C. Apoptosis, necrosis and necroptosis: cell death regulation in the intestinal epithelium. Gut. 2013;62:1062–1071. PubMed

Ahmed FE. Colon cancer: prevalence, screening, gene expression and mutation, and risk factors and assessment. Journal of Environmental Science and Health C: Environmental Carcinogenesis and Ecotoxicology Reviews. 2003;21(2):65–131. PubMed

Grady WM, Carethers JM. Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology. 2008;135(4):1079–1099. PubMed PMC

Lifshitz S, Lamprecht SA, Benharroch D, Prinsloo I, Polak-Charcon S, Schwartz B. Apoptosis (programmed cell death) in colonic cells: from normal to transformed stage. Cancer Letters. 2001;163(2):229–238. PubMed

Zhivotovsky B, Orrenius S. Carcinogenesis and apoptosis: paradigms and paradoxes. Carcinogenesis. 2006;27(10):1939–1945. PubMed

Chen L, Park SM, Tumanov AV, et al. CD95 promotes tumour growth. Nature. 2010;465:492–496. PubMed PMC

Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? The Lancet. 2001;357(9255):539–545. PubMed

Lakatos PL, Lakatos L. Risk for colorectal cancer in ulcerative colitis: changes, causes and management strategies. World Journal of Gastroenterology. 2008;14(25):3937–3947. PubMed PMC

Itzkowitz SH, Yio X. Inflammation and cancer—IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. American Journal of Physiology—Gastrointestinal and Liver Physiology. 2004;287(1):G7–G17. PubMed

Gaur U, Aggarwal BB. Regulation of proliferation, survival and apoptosis by members of the TNF superfamily. Biochemical Pharmacology. 2003;66(8):1403–1408. PubMed

Boyle P, Leon ME. Epidemiology of colorectal cancer. British Medical Bulletin. 2002;64:1–25. PubMed

Yamamoto T, Nakahigashi M, Saniabadi AR. Review article: diet and inflammatory bowel disease—epidemiology and treatment. Alimentary Pharmacology and Therapeutics. 2009;30(2):99–112. PubMed

McEntee MF, Whelan J. Dietary polyunsaturated fatty acids and colorectal neoplasia. Biomedicine and Pharmacotherapy. 2002;56(8):380–387. PubMed

Weijenberg MP, Lüchtenborg M, de Goeij AFPM, et al. Dietary fat and risk of colon and rectal cancer with aberrant MLH1 expression, APC or KRAS genes. Cancer Causes and Control. 2007;18(8):865–879. PubMed PMC

Schrenk D. Dietary fiber, low-molecular-weight food constituents and colo-rectal inflammation in animal models—a review. Molecular Nutrition and Food Research. 2009;53(10):1281–1288. PubMed

Putaala H, Mäkivuokko H, Tiihonen K, Rautonen N. Simulated colon fiber metabolome regulates genes involved in cell cycle, apoptosis, and energy metabolism in human colon cancer cells. Molecular and Cellular Biochemistry. 2011;357(1-2):235–245. PubMed

Sethi G, Shanmugam MK, Ramachandran L, Kumar AP, Tergaonkar V. Multifaceted link between cancer and inflammation. Bioscience Reports. 2012;32(1):1–15. PubMed

Vendramini-Costa DB, Carvalho JE. Molecular link mechanisms between inflammation and cancer. Current Pharmaceutical Design. 2012;18:3831–3852. PubMed

Chiba T, Marusawa H, Ushijima T. Inflammation-associated cancer development in digestive organs: mechanisms and roles for genetic and epigenetic modulation. Gastroenterology. 2012;143:550–563. PubMed

Danese S, Mantovani A. Inflammatory bowel disease and intestinal cancer: a paradigm of the Yin-Yang interplay between inflammation and cancer. Oncogene. 2010;29(23):3313–3323. PubMed

Tappenden KA. Inflammation and intestinal function: where does it start and what does it mean? Journal of Parenteral and Enteral Nutrition. 2008;32(6):648–650. PubMed

Andoh A, Yagi Y, Shioya M, Nishida A, Tsujikawa T, Fujiyama Y. Mucosal cytokine network in inflammatory bowel disease. World Journal of Gastroenterology. 2008;14(33):5154–5161. PubMed PMC

Kraus S, Arber N. Inflammation and colorectal cancer. Current Opinion in Pharmacology. 2009;9(4):405–410. PubMed

Klampfer L. Cytokines, inflammation and colon cancer. Current Cancer Drug Targets. 2011;11(4):451–464. PubMed PMC

Monteleone G, Pallone F, Stolfi C. The dual role of inflammation in colon carcinogenesis. International Journal of Molecular Sciences. 2012;13:11071–11084. PubMed PMC

Rizzo A, Pallone F, Monteleone G, Fantini MC. Intestinal inflammation and colorectal cancer: a doubleedged sword? World Journal of Gastroenterology. 2011;17(26):3092–3100. PubMed PMC

Popivanova BK, Kitamura K, Wu Y, et al. Blocking TNF-α in mice reduces colorectal carcinogenesis associated with chronic colitis. The Journal of Clinical Investigation. 2008;118(2):560–570. PubMed PMC

Waldner MJ, Neurath MF. Cytokines in colitis-associated cancer: potential drug targets? Inflammation and Allergy—Drug Targets. 2008;7(3):187–194. PubMed

Yan SR, Joseph RR, Rosen K, et al. Activation of NF-κB following detachment delays apoptosis in intestinal epithelial cells. Oncogene. 2005;24(43):6482–6491. PubMed PMC

Chapkin RS, Davidson LA, Ly L, Weeks BR, Lupton JR, McMurray DN. Immunomodulatory effects of (n-3) fatty acids: putative link to inflammation and colon cancer. Journal of Nutrition. 2007;137(1):200S–204S. PubMed

McClellan JL, Davis JM, Steiner JL, et al. Intestinal inflammatory cytokine response in relation to tumorigenesis in the Apc Min/+ mouse. Cytokine. 2012;57(1):113–119. PubMed PMC

Aggarwal BB, Gupta SC, Kim JH. Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey. Blood. 2012;119(3):651–665. PubMed PMC

Bhardwaj A, Aggarwal BB. Receptor-mediated choreography of life and death. Journal of Clinical Immunology. 2003;23(5):317–332. PubMed

Walczak H, Krammer PH. The CD95 (APO-1/Fas) and the TRAIL (APO-2L) apoptosis systems. Experimental Cell Research. 2000;256(1):58–66. PubMed

Nagata S. Apoptosis by death factor. Cell. 1997;88(3):355–365. PubMed

MacFarlane M. TRAIL-induced signalling and apoptosis. Toxicology Letters. 2003;139(2-3):89–97. PubMed

Özören N, El-Deiry WS. Defining characteristics of types I and II apoptotic cells in response to TRAIL. Neoplasia. 2002;4(6):551–557. PubMed PMC

Sprick MR, Walczak H. The interplay between the Bcl-2 family and death receptor-mediated apoptosis. Biochimica et Biophysica Acta. 2004;1644(2-3):125–132. PubMed

Wu W, Liu P, Li J. Necroptosis: an emerging form of programmed cell death. Critical Reviews in Oncology/Hematology. 2012;82:249–258. PubMed

Welz PS, Wullaert A, Vlantis K, et al. FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature. 2011;477(7364):330–334. PubMed

Beutler B, Cerami A. Cachectin and tumour necrosis factor as two sides of the same biological coin. Nature. 1986;320(6063):584–588. PubMed

Jäättelä M. Biology of disease: biologic activities and mechanisms of action of tumor necrosis factor-α/cachectin. Laboratory Investigation. 1991;64(6):724–742. PubMed

Tracey KJ, Cerami A. Tumor necrosis factor: a pleiotropic cytokine and therapeutic target. Annual Review of Medicine. 1994;45:491–503. PubMed

Reinecker HC, Steffen M, Witthoeft T, et al. Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1β by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn’s disease. Clinical and Experimental Immunology. 1993;94(1):174–181. PubMed PMC

Scheidereit C. IκB kinase complexes: gateways to NF-κB activation and transcription. Oncogene. 2006;25(51):6685–6705. PubMed

Numata A, Minagawa T, Asano M, Nakane A, Katoh H, Tanabe T. Functional evaluation of tumor-infiltrating mononuclear cells: detection of endogenous interferon-γ and tumor necrosis factor-α in human colorectal adenocarcinomas. Cancer. 1991;68(9):1937–1943. PubMed

Zhang CV. Cell Apoptosis. New York, NY, USA: Nova Science Publishers, Inc.; 2007.

Mellier G, Huang S, Shenoy K, Pervaiz S. TRAILing death in cancer. Molecular Aspects of Medicine. 2010;31(1):93–112. PubMed

Wiley SR, Schooley K, Smolak PJ, et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity. 1995;3(6):673–682. PubMed

Falschlehner C, Schaefer U, Walczak H. Following TRAIL’s path in the immune system. Immunology. 2009;127(2):145–154. PubMed PMC

Mitchell MJ, Wayne E, Rana K, Schaffer CB, King MR. TRAIL-coated leukocytes that kill cancer cells in the circulation. Proceedings of the National Academy of Sciences of the United States of America. 2014;111:930–935. PubMed PMC

Vaculova A, Kaminskyy V, Jalalvand E, Surova O, Zhivotovsky B. Doxorubicin and etoposide sensitize small cell lung carcinoma cells expressing caspase-8 to TRAIL. Molecular Cancer. 2010;9, article 87 PubMed PMC

Secchiero P, Gonelli A, Carnevale E, et al. TRAIL promotes the survival and proliferation of primary human vascular endothelial cells by activating the Akt and ERK pathways. Circulation. 2003;107(17):2250–2256. PubMed

Vaculová A, Hofmanová J, Souček K, Kozubík A. Different modulation of TRAIL-induced apoptosis by inhibition of pro-survival pathways in TRAIL-sensitive and TRAIL-resistant colon cancer cells. FEBS Letters. 2006;580(28-29):6565–6569. PubMed

Vaculová A, Hofmanová J, Zatloukalová J, Kozubík A. Differences in TRAIL-induced changes of Mcl-1 expression among distinct human colon epithelial cell lines. Experimental Cell Research. 2009;315(19):3259–3266. PubMed

Flusberg DA, Roux J, Spencer SL, Sorger PK. Cells surviving fractional killing by TRAIL exhibit transient but sustainable resistance and inflammatory phenotypes. Molecular Biology of the Cell. 2013;24:2186–2200. PubMed PMC

Falschlehner C, Emmerich CH, Gerlach B, Walczak H. TRAIL signalling: decisions between life and death. International Journal of Biochemistry and Cell Biology. 2007;39(7-8):1462–1475. PubMed

Brost S, Koschny R, Sykora J, et al. Differential expression of the TRAIL/TRAIL-receptor system in patients with inflammatory bowel disease. Pathology Research and Practice. 2010;206(1):43–50. PubMed

Koornstra JJ, Kleibeuker JH, van Geelen CMM, et al. Expression of TRAIL (TNF-related apoptosis-inducing ligand) and its receptors in normal colonic mucosa, adenomas, and carcinomas. Journal of Pathology. 2003;200(3):327–335. PubMed

Laguinge LM, Samara RN, Wang W, et al. DR5 receptor mediates anoikis in human colorectal carcinoma cell lines. Cancer Research. 2008;68(3):909–917. PubMed

Grosse-Wilde A, Voloshanenko O, Lawrence Bailey S, et al. TRAIL-R deficiency in mice enhances lymph node metastasis without affecting primary tumor development. The Journal of Clinical Investigation. 2008;118(1):100–110. PubMed PMC

Hoogwater FJH, Nijkamp MW, Smakman N, et al. Oncogenic K-Ras turns death receptors into metastasis-promoting receptors in human and mouse colorectal cancer cells. Gastroenterology. 2010;138(7):2357–2367. PubMed

Hague A, Hicks DJ, Hasan F, et al. Increased sensitivity to TRAIL-induced apoptosis occurs during the adenoma to carcinoma transition of colorectal carcinogenesis. British Journal of Cancer. 2005;92(4):736–742. PubMed PMC

Hofmanová J, Vaculová A, Hyžd’alová M, Kozubík A. Response of normal and colon cancer epithelial cells to TNF-family apoptotic inducers. Oncology Reports. 2008;19:567–573. PubMed

Krammer PH, Arnold R, Lavrik IN. Life and death in peripheral T cells. Nature Reviews Immunology. 2007;7(7):532–542. PubMed

Abrams SI. Positive and negative consequences of Fas/Fas ligand interactions in the antitumor response. Frontiers in Bioscience. 2005;10:809–821. PubMed

Lavrik IN, Krammer PH. Regulation of CD95/Fas signaling at the DISC. Cell Death and Differentiation. 2012;19(1):36–41. PubMed PMC

Zimmerman MA, Singh N, Martin PM, et al. Butyrate suppresses colonic inflammation through HDAC1-dependent Fas upregulation and Fas-mediated apoptosis of T cells. American Journal of Physiology—Gastrointestinal and Liver Physiology. 2012;302(12):G1405–G1415. PubMed PMC

Broad Institute. 2014, http://www.broadinstitute.org/tumorscape/pages/portalHome.jsf.

Ruiz-Ruiz C, Robledo G, Cano E, Redondo JM, Lopez-Rivas A. Characterization of p53-mediated up-regulation of CD95 gene expression upon genotoxic treatment in human breast tumor cells. The Journal of Biological Chemistry. 2003;278(34):31667–31675. PubMed

Paschall AV, Zimmerman MA, Torres CM, et al. Ceramide targets xIAP and cIAP1 to sensitize metastatic colon and breast cancer cells to apoptosis induction to suppress tumor progression. BMC Cancer. 2014;14, article 24 PubMed PMC

Sayani FA, Keenan CM, van Sickle MD, et al. The expression and role of Fas ligand in intestinal inflammation. Neurogastroenterology and Motility. 2004;16(1):61–74. PubMed

Medema JP, de Jong J, van Hall T, Melief CJM, Offringa R. Immune escape of tumors in vivo by expression of cellular FLICE- inhibitory protein. Journal of Experimental Medicine. 1999;190(7):1033–1038. PubMed PMC

Wittkopf N, Gunther C, Martini E, et al. Cellular FLICE-like inhibitory protein secures intestinal epithelial cell survival and immune homeostasis by regulating caspase-8. Gastroenterology. 2013;145(6):1369–1379. PubMed

Liu F, Bardhan K, Yang D, et al. NF-kappaB directly regulates Fas transcription to modulate Fas-mediated apoptosis and tumor suppression. The Journal of Biological Chemistry. 2012;287:25530–25540. PubMed PMC

Simopoulos AP. Omega-3 fatty acids in health and disease and in growth and development. American Journal of Clinical Nutrition. 1991;54(3):438–463. PubMed

Matafome P, Santos-Silva D, Sena CM, Seica R. Common mechanisms of dysfunctional adipose tissue and obesity-related cancers. Diabetes/Metabolism Research and Reviews. 2013;29(4):285–295. PubMed

Day SD, Enos RT, McClellan JL, Steiner JL, Velazquez KT, Murphy EA. Linking inflammation to tumorigenesis in a mouse model of high-fat-diet-enhanced colon cancer. Cytokine. 2013;64:454–462. PubMed PMC

Tammariello AE, Milner JA. Mouse models for unraveling the importance of diet in colon cancer prevention. Journal of Nutritional Biochemistry. 2010;21(2):77–88. PubMed PMC

Zeng H, Lazarova DL. Obesity-related colon cancer: dietary factors and their mechanisms of anticancer action. Clinical and Experimental Pharmacology and Physiology. 2012;39(2):161–167. PubMed

Flachs P, Rossmeisl M, Bryhn M, Kopecky J. Cellular and molecular effects of n-3 polyunsaturated fatty acids on adipose tissue biology and metabolism. Clinical Science. 2009;116(1):1–16. PubMed

Simopoulos AP. Genetic variants in the metabolism of omega-6 and omega-3 fatty acids: their role in the determination of nutritional requirements and chronic disease risk. Experimental Biology and Medicine. 2010;235(7):785–795. PubMed

Simopoulos AP. The importance of the ratio of omega-6/omega-3 essential fatty acids. Biomedicine and Pharmacotherapy. 2002;56(8):365–379. PubMed

Kang JX. Balance of omega-6/omega-3 essential fatty acids is important for health. The evidence from gene transfer studies. World Review of Nutrition and Dietetics. 2005;95:93–102. PubMed

Kremmyda LS, Tvrzicka E, Stankova B, Zak A. Fatty acids as biocompounds: their role in human metabolism, health and disease: a review—part 2: fatty acid physiological roles and applications in human health and disease. Biomedical Papers of the Medical Faculty of the University Palacký, Olomouc, Czechoslovakia. 2011;155(3):195–218. PubMed

D'Archivio M, Scazzocchio B, Giammarioli S, et al. omega3-PUFAs exert anti-inflammatory activity in visceral adipocytes from colorectal cancer patients. PLoS ONE. 2013;8e77432 PubMed PMC

Los DA, Murata N. Membrane fluidity and its roles in the perception of environmental signals. Biochimica et Biophysica Acta. 2004;1666(1-2):142–157. PubMed

Sinicrope FA, Gill S. Role of cyclooxygenase-2 in colorectal cancer. Cancer and Metastasis Reviews. 2004;23(1-2):63–75. PubMed

Medeiros A, Peres-Buzalaf C, Fortino Verdan F, Serezani CH. Prostaglandin E2 and the suppression of phagocyte innate immune responses in different organs. Mediators of Inflammation. 2012;2012:13 pages.327568 PubMed PMC

Barajas-Espinosa A, Ochoa-Cortes F, Moos MP, Ramirez FD, Vanner SJ, Funk CD. Characterization of the cysteinyl leukotriene 2 receptor in novel expression sites of the gastrointestinal tract. American Journal of Pathology. 2011;178(6):2682–2689. PubMed PMC

Hawcroft G, Loadman PM, Belluzzi A, Hull MA. Effect of eicosapentaenoic acid on E-type prostaglandin synthesis and EP4 receptor signaling in human colorectal cancer cells. Neoplasia. 2010;12(8):618–627. PubMed PMC

Serhan CN, Chiang N. Endogenous pro-resolving and anti-inflammatory lipid mediators: a new pharmacologic genus. British Journal of Pharmacology. 2008;153(supplement 1):S200–S215. PubMed PMC

Rudolph IL, Kelley DS, Klasing KC, Erickson KL. Regulation of cellular differentiation and apoptosis by fatty acids and their metabolites. Nutrition Research. 2001;21(1-2):381–393. PubMed

Diggle CP. In vitro studies on the relationship between polyunsaturated fatty acids and cancer: tumour or tissue specific effects? Progress in Lipid Research. 2002;41(3):240–253. PubMed

MacLean CH, Newberry SJ, Mojica WA, et al. Effects of omega-3 fatty acids on cancer risk: a systematic review. Journal of the American Medical Association. 2006;295(4):403–415. PubMed

Moyad MA. An introduction to dietary/supplemental omega-3 fatty acids for general health and prevention—part II. Urologic Oncology: Seminars and Original Investigations. 2005;23(1):36–48. PubMed

Hofmanová J, Souček K, Vaculová A, Kozubík A. Fatty acids in the modulation of reactive oxygen species balance in cancer. In: Valacchi G, Davis PA, editors. Oxidants in Biology: A Question of Balance. chapter 6. Dordrecht, The Netherlands: Springer; 2008. pp. 129–153.

Abir F, Alva S, Kaminski DL, Longo WE. The role of arachidonic acid regulatory enzymes in colorectal disease. Diseases of the Colon and Rectum. 2005;48(7):1471–1483. PubMed

Lanas A, Sopeña F. Nonsteroidal anti-inflammatory drugs and lower gastrointestinal complications. Gastroenterology Clinics of North America. 2009;38(2):333–352. PubMed

Teitelbaum JE, Allan Walker W. Review: the role of omega 3 fatty acids in intestinal inflammation. Journal of Nutritional Biochemistry. 2001;12(1):21–32. PubMed

Jho DH, Cole SM, Lee EM, Espat NJ. Role of omega-3 fatty acid supplementation in inflammation and malignancy. Integrative Cancer Therapies. 2004;3(2):98–111. PubMed

Mills SC, Windsor AC, Knight SC. The potential interactions between polyunsaturated fatty acids and colonic inflammatory processes. Clinical and Experimental Immunology. 2005;142(2):216–228. PubMed PMC

Reddy BS, Burill C, Rigotty J. Effect of diets high in ω-3 and ω6 fatty acids on initiation and postinitiation stages of colon carcinogenesis. Cancer Research. 1991;51(2):487–491. PubMed

Davidson LA, Nguyen DV, Hokanson RM, et al. Chemopreventive n-3 polyunsaturated fatty acids reprogram genetic signatures during colon cancer initiation and progression in the rat. Cancer Research. 2004;64(18):6797–6804. PubMed PMC

Calviello G, Serini S. Dietary Omega-3 Polyunsaturated Fatty Acids and Cancer. New York, NY, USA: Springer; 2010.

Hudert CA, Weylandt KH, Lu Y, et al. Transgenic mice rich in endogenous omega-3 fatty acids are protected from colitis. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(30):11276–11281. PubMed PMC

Pardini RS. Nutritional intervention with omega-3 fatty acids enhances tumor response to anti-neoplastic agents. Chemico-Biological Interactions. 2006;162(2):89–105. PubMed

Surette ME. The science behind dietary omega-3 fatty acids. Canadian Medical Association Journal. 2008;178(2):177–180. PubMed PMC

Calviello G, Serini S, Piccioni E, Pessina G. Antineoplastic effects of N-3 polyunsaturated fatty acids in combination with drugs and radiotherapy: preventive and therapeutic strategies. Nutrition and Cancer. 2009;61(3):287–301. PubMed

de Carlo F, Witte TR, Hardman WE, Claudio PP. Omega-3 eicosapentaenoic acid decreases CD133 colon cancer stem-like cell marker expression while increasing sensitivity to chemotherapy. PLoS ONE. 2013;8e69760 PubMed PMC

Larsson SC, Kumlin M, Ingelman-Sundberg M, Wolk A. Dietary long-chain n-3 fatty acids for the prevention of cancer: a review of potential mechanisms. American Journal of Clinical Nutrition. 2004;79(6):935–945. PubMed

Chapkin RS, Seo J, McMurray DN, Lupton JR. Mechanisms by which docosahexaenoic acid and related fatty acids reduce colon cancer risk and inflammatory disorders of the intestine. Chemistry and Physics of Lipids. 2008;153(1):14–23. PubMed PMC

Skender B, Vaculová AH, Hofmanová J. Docosahexaenoic fatty acid (DHA) in the regulation of colon cell growth and cell death: a review. Biomedical Papers of the Medical Faculty of the University Palacký, Olomouc, Czechoslovakia. 2012;156(3):186–199. PubMed

Kaczmarczyk MM, Miller MJ, Freund GG. The health benefits of dietary fiber: beyond the usual suspects of type 2 diabetes mellitus, cardiovascular disease and color cancer. Metabolism: Clinical and Experimental. 2012;61:1058–1066. PubMed PMC

Hamer HM, Jonkers D, Venema K, Vanhoutvin S, Troost FJ, Brummer R-J. Review article: the role of butyrate on colonic function. Alimentary Pharmacology and Therapeutics. 2008;27(2):104–119. PubMed

Hofmanová J, Vaculová A, Kozubík A. Regulation of the metabolism of polyunsaturated fatty acids and butyrate in colon cancer cells. Current Pharmaceutical Biotechnology. 2013;14(3):274–288. PubMed

Tong X, Yin L, Giardina C. Butyrate suppresses Cox-2 activation in colon cancer cells through HDAC inhibition. Biochemical and Biophysical Research Communications. 2004;317(2):463–471. PubMed

Ventham NT, Kennedy NA, Nimmo ER, Satsangi J. Beyond gene discovery in inflammatory bowel disease: the emerging role of epigenetics. Gastroenterology. 2013;145:293–308. PubMed PMC

Daroqui MC, Augenlicht LH. Transcriptional attenuation in colon carcinoma cells in response to butyrate. Cancer Prevention Research. 2010;3(10):1292–1302. PubMed PMC

Canani RB, Costanzo MD, Leone L, Pedata M, Meli R, Calignano A. Potential beneficial effects of butyrate in intestinal and extraintestinal diseases. World Journal of Gastroenterology. 2011;17(12):1519–1528. PubMed PMC

Ganapathy V, Thangaraju M, Gopal E, et al. Sodium-coupled monocarboxylate transporters in normal tissues and in cancer. AAPS Journal. 2008;10(1):193–199. PubMed PMC

Karaki SI, Tazoe H, Hayashi H, et al. Expression of the short-chain fatty acid receptor, GPR43, in the human colon. Journal of Molecular Histology. 2008;39(2):135–142. PubMed

Thibault R, Blachier F, Darcy-Vrillon B, de Coppet P, Bourreille A, Segain J-P. Butyrate utilization by the colonic mucosa in inflammatory bowel diseases: a transport deficiency. Inflammatory Bowel Diseases. 2010;16(4):684–695. PubMed

Andriamihaja M, Chaumontet C, Tome D, Blachier F. Butyrate metabolism in human colon carcinoma cells: implications concerning its growth-inhibitory effect. Journal of Cellular Physiology. 2009;218(1):58–65. PubMed

Vondráček J, Sheard MA, Krejčí P, Minksová K, Hofmanová J, Kozubík A. Modulation of death receptor-mediated apoptosis in differentiating human myeloid leukemia HL-60 cells. Journal of Leukocyte Biology. 2001;69:794–802. PubMed

Štika J, Vondráček J, Hofmanová J, Šimek V, Kozubík A. MK-886 enhances tumour necrosis factor-alpha-induced differentiation and apoptosis. Cancer Letters. 2006;237:263–271. PubMed

Procházková J, Stixová L, Souček K, Hofmanová J, Kozubík A. Monocytic differentiation of leukemic HL-60 cells induced by co-treatment with TNF-α and MK886 requires activation of pro-apoptotic machinery. European Journal of Haematology. 2009;83(1):35–47. PubMed

Kovaříková M, Hofmanová J, Souček K, Kozubík A. The effects of TNF-α and inhibitors of arachidonic acid metabolism on human colon HT-29 cells depend on differentiation status. Differentiation. 2004;72(1):23–31. PubMed

Hofmanová J, Vaculová A, Kozubík A. Polyunsaturated fatty acids sensitize human colon adenocarcinoma HT-29 cells to death receptor-mediated apoptosis. Cancer Letters. 2005;218(1):33–41. PubMed

Vaculová A, Hofmanová J, Anděra L, Kozubík A. TRAIL and docosahexaenoic acid cooperate to induce HT-29 colon cancer cell death. Cancer Letters. 2005;229:43–48. PubMed

Vondálová Blanářová O, Jelínková I, Szöor A, et al. Cisplatin and a potent platinum(IV) complex-mediated enhancement of TRAIL-induced cancer cells killing is associated with modulation of upstream events in the extrinsic apoptotic pathway. Carcinogenesis. 2011;32(1):42–51. PubMed

Hofmanová J, Vaculová A, Koubková Z, Hýžďalová M, Kozubík A. Human fetal colon cells and colon cancer cells respond differently to butyrate and PUFAs. Molecular Nutrition & Food Research. 2009;53(supplement 1):S102–S113. PubMed

Kočí L, Hýžd’alová M, Vaculová A, Hofmanová J, Kozubík A. Detachment-mediated resistance to TRAIL-induced apoptosis is associated with stimulation of the PI3K/Akt pathway in fetal and adenocarcinoma epithelial colon cells. Cytokine. 2011;55(1):34–39. PubMed

Accioly MT, Pacheco P, Maya-Monteiro CM, et al. Lipid bodies are reservoirs of cyclooxygenase-2 and sites of prostaglandin-E2 synthesis in colon cancer cells. Cancer Research. 2008;68(6):1732–1740. PubMed

Ma DWL, Seo J, Davidson LA, et al. n-3 PUFA alter caveolae lipid composition and resident protein localization in mouse colon. The FASEB Journal. 2004;18(9):1040–1042. PubMed

Stillwell W, Shaikh SR, Zerouga M, Siddiqui R, Wassal SR. Docosahexaenoic acid affects cell signaling by altering lipid rafts. Reproduction Nutrition Development. 2005;45(5):559–579. PubMed

Seo J, Barhoumi R, Johnson AE, Lupton JR, Chapkin RS. Docosahexaenoic acid selectively inhibits plasma membrane targeting of lipidated proteins. The FASEB Journal. 2006;20(6):770–772. PubMed

Rogers KR, Kikawa KD, Mouradian M, et al. Docosahexaenoic acid alters epidermal growth factor receptor-related signaling by disrupting its lipid raft association. Carcinogenesis. 2010;31(9):1523–1530. PubMed

Kagan VE, Tyurina YY, Bayir H, et al. The “pro-apoptotic genies” get out of mitochondria: oxidative lipidomics and redox activity of cytochrome c/cardiolipin complexes. Chemico-Biological Interactions. 2006;163(1-2):15–28. PubMed

Rohrbach S. Effects of dietary polyunsaturated fatty acids on mitochondria. Current Pharmaceutical Design. 2009;15(36):4103–4116. PubMed

Hong MY, Chapkin RS, Barhoumi R, et al. Fish oil increases mitochondrial phospholipid unsaturation, upregulating reactive oxygen species and apoptosis in rat colonocytes. Carcinogenesis. 2002;23(11):1919–1925. PubMed

Mbodji K, Charpentier C, Guerin C, et al. Adjunct therapy of n-3 fatty acids to 5-ASA ameliorates inflammatory score and decreases NF-kappaB in rats with TNBS-induced colitis. The Journal of Nutritional Biochemistry. 2013;24:700–705. PubMed

Gravaghi C, la Perle KMD, Ogrodwski P, et al. Cox-2 expression, PGE2 and cytokines production are inhibited by endogenously synthesized n-3 PUFAs in inflamed colon of fat-1 mice. Journal of Nutritional Biochemistry. 2011;22(4):360–365. PubMed

Algamas-Dimantov A, Davidovsky D, Ben-Ari J, et al. Amelioration of diabesity-induced colorectal ontogenesis by omega-3 fatty acids in mice. The Journal of Lipid Research. 2012;53:1056–1070. PubMed PMC

Meydani SN. Dietary modulation of cytokine production and biologic functions. Nutrition Reviews. 1990;48(10):361–369. PubMed

Ribardo DA, Peterson JW, Chopra AK. Phospholipase A2-activating protein—an important regulatory molecule in modulating cyclooxygenase-2 and tumor necrosis factor production during inflammation. Indian Journal of Experimental Biology. 2002;40(2):129–138. PubMed

Sassa T, Suto S, Okayasu Y, Kihara A. A shift in sphingolipid composition from C24 to C16 increases susceptibility to apoptosis in HeLa cells. Biochimica et Biophysica Acta. 2012;1821(7):1031–1037. PubMed

Hayakawa M, Ishida N, Takeuchi K, et al. Arachidonic acid-selective cytosolic phospholipase A2 is crucial in the cytotoxic action of tumor necrosis factor. The Journal of Biological Chemistry. 1993;268(15):11290–11295. PubMed

Cao Y, Pearman AT, Zimmerman GA, McIntyre TM, Prescott SM. Intracellular unesterified arachidonic acid signals apoptosis. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(21):11280–11285. PubMed PMC

Bannenberg GL. Therapeutic applicability of anti-inflammatory and proresolving polyunsaturated fatty acid-derived lipid mediators. TheScientificWorldJOURNAL. 2010;10:676–712. PubMed PMC

Kinsella JE. Lipids, membrane receptors, and enzymes: effects of dietary fatty acids. Journal of Parenteral and Enteral Nutrition. 1990;14(5):200S–217S. PubMed

di Marzo V. Arachidonic acid and eicosanoids as targets and effectors in second messenger interactions. Prostaglandins Leukotrienes and Essential Fatty Acids. 1995;53(4):239–254. PubMed

Nowak J, Weylandt KH, Habbel P, et al. Colitis-associated colon tumorigenesis is suppressed in transgenic mice rich in endogenous n-3 fatty acids. Carcinogenesis. 2007;28(9):1991–1995. PubMed

Sampath H, Ntambi JM. Polyunsaturated fatty acid regulation of genes of lipid metabolism. Annual Review of Nutrition. 2005;25:317–340. PubMed

Edwards IJ, O’Flaherty JT. Omega-3 fatty acids and PPAR γ in cancer. PPAR Research. 2008;2008:14 pages.358052 PubMed PMC

Kliewer SA, Sundseth SS, Jones SA, et al. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ . Proceedings of the National Academy of Sciences of the United States of America. 1997;94(9):4318–4323. PubMed PMC

Han J, Soletti RC, Sadarangani A, et al. Nuclear expression of beta-catenin promotes RB stability and resistance to TNF-induced apoptosis in colon cancer cells. Molecular Cancer Research. 2013;11:207–218. PubMed PMC

Narayanan BA, Narayanan NK, Simi B, Reddy BS. Modulation of inducible nitric oxide synthase and related proinflammatory genes by the omega-3 fatty acid docosahexaenoic acid in human colon cancer cells. Cancer Research. 2003;63(5):972–979. PubMed

Hernandez A, Thomas R, Smith F, et al. Butyrate sensitizes human colon cancer cells to TRAIL-mediated apoptosis. Surgery. 2001;130(2):265–272. PubMed

Ruemmele FM, Dionne S, Qureshi I, Sarma DSR, Levy E, Seidman EG. Butyrate mediates Caco-2 cell apoptosis via up-regulation of pro-apoptotic BAK and inducing caspase-3 mediated cleavage of poly-(ADP-ribose) polymerase (PARP) Cell Death and Differentiation. 1999;6(8):729–735. PubMed

Jones SA, Butler RN, Sanderson IR, Wilson JW. The effect of specific caspase inhibitors on TNF-α and butyrate-induced apoptosis of intestinal epithelial cells. Experimental Cell Research. 2004;292(1):29–39. PubMed

Orzechowska S, Pajak B, Gajkowska B, Orzechowski A. Cholesterol level determines viability and mitogenicity, but it does not affect sodium butyrate-dependent sensitization of Colo 205 cells to TNF-α-induced apoptosis. Oncology Reports. 2011;25(2):573–582. PubMed

Tran SEF, Holmström TH, Ahonen M, Kähäri V-M, Eriksson JE. MAPK/ERK overrides the apoptotic signaling from Fas, TNF, and TRAIL receptors. The Journal of Biological Chemistry. 2001;276(19):16484–16490. PubMed

Giardina C, Boulares H, Inan MS. NSAIDs and butyrate sensitize a human colorectal cancer cell line to TNF-α and Fas ligation: the role of reactive oxygen species. Biochimica et Biophysica Acta. 1999;1448(3):425–438. PubMed

Kovaříková M, Pacherník J, Hofmanová J, Zadák Z, Kozubík A. TNF-alpha modulates the differentiation induced by butyrate in the HT-29 human colon adenocarcinoma cell line. European Journal of Cancer. 2000;36(14):1844–1852. PubMed

Gong J, Yang D, Kohanim S, Humphreys R, Broemeling L, Kurzrock R. Novel in vivo imaging shows up-regulation of death receptors by paclitaxel and correlates with enhanced antitumor effects of receptor agonist antibodies. Molecular Cancer Therapeutics. 2006;5(12):2991–3000. PubMed

Pajak B, Gajkowska B, Orzechowski A. Position of STAT-1α in cycloheximide-dependent apoptosis triggered by TNF-α in human colorectal COLO 205 cancer cell line; role of polyphenolic compounds. Journal of Physiology and Pharmacology. 2005;56(supplement 3):119–141. PubMed

Lombard MA, Wallace TL, Kubicek MF, et al. Synthetic matrix metalloproteinase inhibitors and tissue inhibitor of metalloproteinase (TIMP)-2, but not TIMP-1, inhibit shedding of tumor necrosis factor-α receptors in a human colon adenocarcinoma (Colo 205) cell line. Cancer Research. 1998;58(17):4001–4007. PubMed

Pajak B, Gajkowska B, Orzechowski A. Cycloheximide-mediated sensitization to TNF-α-induced apoptosis in human colorectal cancer cell line COLO 205; role of FLIP and metabolic inhibitors. Journal of Physiology and Pharmacology. 2005;56(supplement 3):101–118. PubMed

Pajak B, Orzechowski A. IFN-alpha competes with TNF-alpha for STAT-1alpha; molecular basis for immune escape of human colon adenocarcinoma COLO 205 cells. Oncology Reports. 2007;18(4):1039–1045. PubMed

Cesaro P, Raiteri E, Démoz M, et al. Expression of protein kinase C β1 confers resistance to TNFα- and paclitaxel-induced apoptosis in HT-29 colon carcinoma cells. International Journal of Cancer. 2001;93(2):179–184. PubMed

Velázquez OC, Seto RW, Rombeau JL. The scientific rationale and clinical application of short-chain fatty acids and medium-chain triacylglycerols. Proceedings of the Nutrition Society. 1996;55(1):49–78. PubMed

Inan MS, Rasoulpour RJ, Yin L, Hubbard AK, Rosenberg DW, Giardina C. The luminal short-chain fatty acid butyrate modulates NF-κB activity in a human colonic epithelial cell line. Gastroenterology. 2000;118(4):724–734. PubMed

Yin L, Laevsky G, Giardina C. Butyrate suppression of colonocyte NF-κ B activation and cellular proteasome activity. The Journal of Biological Chemistry. 2001;276(48):44641–44646. PubMed

Hýžd’alová M, Hofmanová J, Pacherník J, Vaculová A, Kozubík A. The interaction of butyrate with TNF-alpha during differentiation and apoptosis of colon epithelial cells: role of NF-kappaB activation. Cytokine. 2008;44:33–43. PubMed

Butzner JD, Parmar R, Bell CJ, Dalal V. Butyrate enema therapy stimulates mucosal repair in experimental colitis in the rat. Gut. 1996;38(4):568–573. PubMed PMC

Segain JP, Raingeard de la Blétière D, Bourreille A, et al. Butyrate inhibits inflammatory responses through NFκB inhibition: implications for Crohn’s disease. Gut. 2000;47(3):397–403. PubMed PMC

Kim YH, Park JW, Lee JY, Kwon TK. Sodium butyrate sensitizes TRAIL-mediated apoptosis by induction of transcription from the DR5 gene promoter through Sp1 sites in colon cancer cells. Carcinogenesis. 2004;25(10):1813–1820. PubMed

Hamed HA, Yamaguchi Y, Fisher PB, Grant S, Dent P. Sorafenib and HDAC inhibitors synergize with TRAIL to kill tumor cells. Journal of Cellular Physiology. 2013;228(10):1996–2005. PubMed PMC

Earel JK, Jr., VanOosten RL, Griffith TS. Histone deacetylase inhibitors modulate the sensitivity of tumor necrosis factor-related apoptosis-inducing ligand-resistant bladder tumor cells. Cancer Research. 2006;66(1):499–507. PubMed

Bangert A, Cristofanon S, Eckhardt I, et al. Histone deacetylase inhibitors sensitize glioblastoma cells to TRAIL-induced apoptosis by c-myc-mediated downregulation of cFLIP. Oncogene. 2012;31:4677–4688. PubMed

Giardina C, Inan MS. Nonsteroidal anti-inflammatory drugs, short-chain fatty acids, and reactive oxygen metabolism in human colorectal cancer cells. Biochimica et Biophysica Acta. 1998;1401(3):277–288. PubMed

Dupertuis YM, Meguid MM, Pichard C. Advancing from immunonutrition to a pharmaconutrition: a gigantic challenge. Current Opinion in Clinical Nutrition and Metabolic Care. 2009;12(4):398–403. PubMed

Lands B. A critique of paradoxes in current advice on dietary lipids. Progress in Lipid Research. 2008;47(2):77–106. PubMed

Hagi A, Nakayama M, Shinzaki W, Haji S, Ohyanagi H. Effects of the ω-6:ω-3 fatty acid ratio of fat emulsions on the fatty acid composition in cell membranes and the anti-inflammatory action. Journal of Parenteral and Enteral Nutrition. 2010;34(3):263–270. PubMed

Han YY, Lai SL, Ko WJ, Chou CH, Lai HS. Effects of fish oil on inflammatory modulation in surgical intensive care unit patients. Nutrition in Clinical Practice. 2012;27(1):91–98. PubMed

Wanten GJA, Calder PC. Immune modulation by parenteral lipid emulsions. American Journal of Clinical Nutrition. 2007;85(5):1171–1184. PubMed

Berquin IM, Edwards IJ, Chen YQ. Multi-targeted therapy of cancer by omega-3 fatty acids. Cancer Letters. 2008;269(2):363–377. PubMed PMC

Calder PC. Symposium 4: hot topics in parenteral nutrition. Rationale for using new lipid emulsions in parenteral nutrition and a review of the trials performed in adults. Proceedings of the Nutrition Society. 2009;68(3):252–260. PubMed

Waitzberg DL, Torrinhas RS. Fish oil lipid emulsions and immune response: what clinicians need to know. Nutrition in Clinical Practice. 2009;24(4):487–499. PubMed

van Beelen VA, Spenkelink B, Mooibroek H, et al. An n-3 PUFA-rich microalgal oil diet protects to a similar extent as a fish oil-rich diet against AOM-induced colonic aberrant crypt foci in F344 rats. Food and Chemical Toxicology. 2009;47(2):316–320. PubMed

Russell FD, Burgin-Maunder CS. Distinguishing health benefits of eicosapentaenoic and docosahexaenoic acids. Marine Drugs. 2012;10:2535–2559. PubMed PMC

Garib R, Garla P, Torrinhas RS, Bertevello PL, Logullo AF, Waitzberg DL. Effects of parenteral fish oil lipid emulsions on colon morphology and cytokine expression after experimental colitis. Nutrición Hospitalaria. 2013;28(3):849–856. PubMed

Tisdale MJ. The ‘cancer cachectic factor’. Supportive Care in Cancer. 2003;11(2):73–78. PubMed

Pajak B, Orzechowska S, Pijet B, et al. Crossroads of cytokine signaling—the chase to stop muscle cachexia. Journal of Physiology and Pharmacology. 2008;59(supplement 9):251–264. PubMed

Deans C, Wigmore SJ. Systemic inflammation, cachexia and prognosis in patients with cancer. Current Opinion in Clinical Nutrition and Metabolic Care. 2005;8(3):265–269. PubMed

Balkwill F. TNF-α in promotion and progression of cancer. Cancer and Metastasis Reviews. 2006;25(3):409–416. PubMed

Raqib R, Sarker P, Mily A, et al. Efficacy of sodium butyrate adjunct therapy in shigellosis: a randomized, double-blind, placebo-controlled clinical trial. BMC Infectious Diseases. 2012;12, article 111 PubMed PMC

Dietary fatty acids specifically modulate phospholipid pattern in colon cells with distinct differentiation capacities