Abstract
The omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) has anti-inflammatory and anti-cancer properties. Among pro-inflammatory mediators, tumor necrosis factor α (TNFα) plays a paradoxical role in cancer biology with induction of cancer cell death or survival depending on the cellular context. The objective of the study was to evaluate the role of TNFα in DHA-mediated tumor growth inhibition and colon cancer cell death. The treatment of human colorectal cancer cells, HCT-116 and HCT-8 cells, with DHA triggered apoptosis in autocrine TNFα-dependent manner. We demonstrated that DHA-induced increased content of TNFα mRNA occurred through a post-transcriptional regulation via the down-regulation of microRNA-21 (miR-21) expression. Treatment with DHA led to nuclear accumulation of Foxo3a that bounds to the miR-21 promoter triggering its transcriptional repression. Moreover, inhibition of RIP1 kinase and AMP-activated protein kinase α reduced Foxo3a nuclear-cytoplasmic shuttling and subsequent increase of TNFα expression through a decrease of miR-21 expression in DHA-treated colon cancer cells. Finally, we were able to show in HCT-116 xenograft tumor-bearing nude mice that a DHA-enriched diet induced a decrease of human miR-21 expression and an increase of human TNFα mRNA expression limiting tumor growth in a cancer cell-derived TNFα dependent manner. Altogether, the present work highlights a novel mechanism for anti-cancer action of DHA involving colon cancer cell death mediated through autocrine action of TNFα.
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References
Jasperson KW, Tuohy TM, Neklason DW, Burt RW . Hereditary and familial colon cancer. Gastroenterology 2010; 138: 2044–2058.
Beaugerie L, Itzkowitz SH . Cancers complicating inflammatory bowel disease. N Engl J Med 2015; 372: 1441–1452.
Brenner H, Kloor M, Pox CP . Colorectal cancer. Lancet 2014; 383: 1490–1502.
Krzystek-Korpacka M, Diakowska D, Kapturkiewicz B, Bebenek M, Gamian A . Profiles of circulating inflammatory cytokines in colorectal cancer (CRC), high cancer risk conditions, and health are distinct. Possible implications for CRC screening and surveillance. Cancer Lett 2013; 337: 107–114.
Maihofner C, Charalambous MP, Bhambra U, Lightfoot T, Geisslinger G, Gooderham NJ . Expression of cyclooxygenase-2 parallels expression of interleukin-1beta, interleukin-6 and NF-kappaB in human colorectal cancer. Carcinogenesis 2003; 24: 665–671.
Anti M, Marra G, Armelao F, Bartoli GM, Ficarelli R, Percesepe A et al. Effect of omega-3 fatty acids on rectal mucosal cell proliferation in subjects at risk for colon cancer. Gastroenterology 1992; 103: 883–891.
Bartoli GM, Palozza P, Marra G, Armelao F, Franceschelli P, Luberto C et al. n-3 PUFA and alpha-tocopherol control of tumor cell proliferation. Mol Aspects Med 1993; 14: 247–252.
Anti M, Armelao F, Marra G, Percesepe A, Bartoli GM, Palozza P et al. Effects of different doses of fish oil on rectal cell proliferation in patients with sporadic colonic adenomas. Gastroenterology 1994; 107: 1709–1718.
Cockbain AJ, Toogood GJ, Hull MA . Omega-3 polyunsaturated fatty acids for the treatment and prevention of colorectal cancer. Gut 2012; 61: 135–149.
Bathen TF, Holmgren K, Lundemo AG, Hjelstuen MH, Krokan HE, Gribbestad IS et al. Omega-3 fatty acids suppress growth of SW620 human colon cancer xenografts in nude mice. Anticancer Res 2008; 28: 3717–3723.
Calviello G, Di Nicuolo F, Gragnoli S, Piccioni E, Serini S, Maggiano N et al. n-3 PUFAs reduce VEGF expression in human colon cancer cells modulating the COX-2/PGE2 induced ERK-1 and -2 and HIF-1alpha induction pathway. Carcinogenesis 2004; 25: 2303–2310.
Berger H, Vegran F, Chikh M, Gilardi F, Ladoire S, Bugaut H et al. SOCS3 transactivation by PPARgamma prevents IL-17-driven cancer growth. Cancer Res 2013; 73: 3578–3590.
Gravaghi C, La Perle KM, Ogrodwski P, Kang JX, Quimby F, Lipkin M et al. Cox-2 expression, PGE(2) and cytokines production are inhibited by endogenously synthesized n-3 PUFAs in inflamed colon of fat-1 mice. J Nutr Biochem 2011; 22: 360–365.
Liang B, Wang S, Ye YJ, Yang XD, Wang YL, Qu J et al. Impact of postoperative omega-3 fatty acid-supplemented parenteral nutrition on clinical outcomes and immunomodulations in colorectal cancer patients. World J Gastroenterol 2008; 14: 2434–2439.
Yao L, Han C, Song K, Zhang J, Lim K, Wu T . Omega-3 Polyunsaturated Fatty Acids Upregulate 15-PGDH Expression in Cholangiocarcinoma Cells by Inhibiting miR-26a/b Expression. Cancer Res 2015; 75: 1388–1398.
Naylor MS, Stamp GW, Balkwill FR . Investigation of cytokine gene expression in human colorectal cancer. Cancer Res 1990; 50: 4436–4440.
Popivanova BK, Kitamura K, Wu Y, Kondo T, Kagaya T, Kaneko S et al. Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis. J Clin Invest 2008; 118: 560–570.
Zins K, Abraham D, Sioud M, Aharinejad S . Colon cancer cell-derived tumor necrosis factor-alpha mediates the tumor growth-promoting response in macrophages by up-regulating the colony-stimulating factor-1 pathway. Cancer Res 2007; 67: 1038–1045.
Balkwill FR, Lee A, Aldam G, Moodie E, Thomas JA, Tavernier J et al. Human tumor xenografts treated with recombinant human tumor necrosis factor alone or in combination with interferons. Cancer Res 1986; 46: 3990–3993.
Kreeger PK, Mandhana R, Alford SK, Haigis KM, Lauffenburger DA . RAS mutations affect tumor necrosis factor-induced apoptosis in colon carcinoma cells via ERK-modulatory negative and positive feedback circuits along with non-ERK pathway effects. Cancer Res 2009; 69: 8191–8199.
Wang P, Qiu W, Dudgeon C, Liu H, Huang C, Zambetti GP et al. PUMA is directly activated by NF-kappaB and contributes to TNF-alpha-induced apoptosis. Cell Death Differ 2009; 16: 1192–1202.
Cianchi F, Papucci L, Schiavone N, Lulli M, Magnelli L, Vinci MC et al. Cannabinoid receptor activation induces apoptosis through tumor necrosis factor alpha-mediated ceramide de novo synthesis in colon cancer cells. Clin Cancer Res 2008; 14: 7691–7700.
Petersen SL, Wang L, Yalcin-Chin A, Li L, Peyton M, Minna J et al. Autocrine TNFalpha signaling renders human cancer cells susceptible to Smac-mimetic-induced apoptosis. Cancer Cell 2007; 12: 445–456.
Ofengeim D, Yuan J . Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death. Nat Rev Mol Cell Biol 2013; 14: 727–736.
Giros A, Grzybowski M, Sohn VR, Pons E, Fernandez-Morales J, Xicola RM et al. Regulation of colorectal cancer cell apoptosis by the n-3 polyunsaturated fatty acids Docosahexaenoic and Eicosapentaenoic. Cancer Prev Res (Phila) 2009; 2: 732–742.
Biton S, Ashkenazi A . NEMO and RIP1 control cell fate in response to extensive DNA damage via TNF-alpha feedforward signaling. Cell 2011; 145: 92–103.
van Kouwenhove M, Kedde M, Agami R . MicroRNA regulation by RNA-binding proteins and its implications for cancer. Nat Rev Cancer 2011; 11: 644–656.
Farago N, Feher LZ, Kitajka K, Das UN, Puskas LG . MicroRNA profile of polyunsaturated fatty acid treated glioma cells reveal apoptosis-specific expression changes. Lipids Health Dis 2011; 10: 173.
Gil-Zamorano J, Martin R, Daimiel L, Richardson K, Giordano E, Nicod N et al. Docosahexaenoic acid modulates the enterocyte Caco-2 cell expression of microRNAs involved in lipid metabolism. J Nutr 2014; 144: 575–585.
Zhang X, Ng WL, Wang P, Tian L, Werner E, Wang H et al. MicroRNA-21 modulates the levels of reactive oxygen species by targeting SOD3 and TNFalpha. Cancer Res 2012; 72: 4707–4713.
Wang K, Li PF . Foxo3a regulates apoptosis by negatively targeting miR-21. J Biol Chem 2010; 285: 16958–16966.
Greer EL, Oskoui PR, Banko MR, Maniar JM, Gygi MP, Gygi SP et al. The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J Biol Chem 2007; 282: 30107–30119.
Chung H, Lee YS, Mayoral R, Oh DY, Siu JT, Webster NJ et al. Omega-3 fatty acids reduce obesity-induced tumor progression independent of GPR120 in a mouse model of postmenopausal breast cancer. Oncogene 2014; 34: 3504–3513.
Al-Zoubi M, Salem AF, Martinez-Outschoorn UE, Whitaker-Menezes D, Lamb R, Hulit J et al. Creating a tumor-resistant microenvironment: cell-mediated delivery of TNFalpha completely prevents breast cancer tumor formation in vivo. Cell Cycle 2013; 12: 480–490.
Shime H, Matsumoto M, Oshiumi H, Tanaka S, Nakane A, Iwakura Y et al. Toll-like receptor 3 signaling converts tumor-supporting myeloid cells to tumoricidal effectors. Proc Natl Acad Sci USA 2012; 109: 2066–2071.
Bansal T, Alaniz RC, Wood TK, Jayaraman A . The bacterial signal indole increases epithelial-cell tight-junction resistance and attenuates indicators of inflammation. Proc Natl Acad Sci USA 2010; 107: 228–233.
Verbeke H, De Hertogh G, Li S, Vandercappellen J, Noppen S, Schutyser E et al. Expression of angiostatic platelet factor-4var/CXCL4L1 counterbalances angiogenic impulses of vascular endothelial growth factor, interleukin-8/CXCL8, and stromal cell-derived factor 1/CXCL12 in esophageal and colorectal cancer. Human Pathol 2010; 41: 990–1001.
Christofferson DE, Li Y, Hitomi J, Zhou W, Upperman C, Zhu H et al. A novel role for RIP1 kinase in mediating TNFalpha production. Cell Death Dis 2012; 3: e320.
Yu X, Deng Q, Li W, Xiao L, Luo X, Liu X et al. Neoalbaconol induces cell death through necroptosis by regulating RIPK-dependent autocrine TNFalpha and ROS production. Oncotarget 2015; 6: 1995–2008.
O'Donnell MA, Perez-Jimenez E, Oberst A, Ng A, Massoumi R, Xavier R et al. Caspase 8 inhibits programmed necrosis by processing CYLD. Nat Cell Biol 2011; 13: 1437–1442.
Shalini S, Dorstyn L, Dawar S, Kumar S . Old, new and emerging functions of caspases. Cell Death Differ 2015; 22: 526–539.
Varga T, Czimmerer Z, Nagy L . PPARs are a unique set of fatty acid regulated transcription factors controlling both lipid metabolism and inflammation. Biochim Biophys Acta 2011; 1812: 1007–1022.
Calviello G, Resci F, Serini S, Piccioni E, Toesca A, Boninsegna A et al. Docosahexaenoic acid induces proteasome-dependent degradation of beta-catenin, down-regulation of survivin and apoptosis in human colorectal cancer cells not expressing COX-2. Carcinogenesis 2007; 28: 1202–1209.
Yu H, Liu Y, Pan W, Shen S, Das UN . Polyunsaturated fatty acids augment tumoricidal action of 5-fluorouracil on gastric cancer cells by their action on vascular endothelial growth factor, tumor necrosis factor-alpha and lipid metabolism related factors. Arch Med Sci 2015; 11: 282–291.
Martinasso G, Oraldi M, Trombetta A, Maggiora M, Bertetto O, Canuto RA et al. Involvement of PPARs in cell proliferation and apoptosis in human colon cancer specimens and in normal and cancer cell lines. PPAR Res 2007; 2007: 93416.
Sun H, Berquin IM, Owens RT, O'Flaherty JT, Edwards IJ . Peroxisome proliferator-activated receptor gamma-mediated up-regulation of syndecan-1 by n-3 fatty acids promotes apoptosis of human breast cancer cells. Cancer Res 2008; 68: 2912–2919.
Begin ME, Das UN, Ells G, Horrobin DF . Selective killing of human cancer cells by polyunsaturated fatty acids. Prostaglandins Leukot Med 1985; 19: 177–186.
Begin ME, Ells G, Das UN, Horrobin DF . Differential killing of human carcinoma cells supplemented with n-3 and n-6 polyunsaturated fatty acids. J Natl Cancer Inst 1986; 77: 1053–1062.
Béguin ME, Das UN, Ells G . Cytotoxic effects of essential fatty acids (EFA) in mixed cultures of normal and malignant human cells. Prog Lipid Res 1986; 25: 573–576.
Das UN . Tumoricidal action of cis-unsaturated fatty acids and their relationship to free radicals and lipid peroxidation. Cancer Lett 1991; 56: 235–243.
Monjazeb AM, High KP, Connoy A, Hart LS, Koumenis C, Chilton FH . Arachidonic acid-induced gene expression in colon cancer cells. Carcinogenesis 2006; 27: 1950–1960.
Bartoli R, Fernandez-Banares F, Navarro E, Castella E, Mane J, Alvarez M et al. Effect of olive oil on early and late events of colon carcinogenesis in rats: modulation of arachidonic acid metabolism and local prostaglandin E(2) synthesis. Gut 2000; 46: 191–199.
Zou Z, Bellenger S, Massey KA, Nicolaou A, Geissler A, Bidu C et al. Inhibition of the HER2 pathway by n-3 polyunsaturated fatty acids prevents breast cancer in fat-1 transgenic mice. J Lipid Res 2013; 54: 3453–3463.
Schetter AJ, Nguyen GH, Bowman ED, Mathe EA, Yuen ST, Hawkes JE et al. Association of inflammation-related and microRNA gene expression with cancer-specific mortality of colon adenocarcinoma. Clin Cancer Res 2009; 15: 5878–5887.
Gattolliat CH, Uguen A, Pesson M, Trillet K, Simon B, Doucet L et al. MicroRNA and targeted mRNA expression profiling analysis in human colorectal adenomas and adenocarcinomas. Eur J Cancer 2015; 51: 409–420.
Iliopoulos D, Jaeger SA, Hirsch HA, Bulyk ML, Struhl K . STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Mol Cell 2010; 39: 493–506.
Zhou R, Hu G, Gong AY, Chen XM . Binding of NF-kappaB p65 subunit to the promoter elements is involved in LPS-induced transactivation of miRNA genes in human biliary epithelial cells. Nucleic Acids Res 2010; 38: 3222–3232.
Chiacchiera F, Simone C . The AMPK-FoxO3A axis as a target for cancer treatment. Cell Cycle 2010; 9: 1091–1096.
Chou CC, Lee KH, Lai IL, Wang D, Mo X, Kulp SK et al. AMPK reverses the mesenchymal phenotype of cancer cells by targeting the Akt-MDM2-Foxo3a signaling axis. Cancer Res 2014; 74: 4783–4795.
Gu Z, Wu J, Wang S, Suburu J, Chen H, Thomas MJ et al. Polyunsaturated fatty acids affect the localization and signaling of PIP3/AKT in prostate cancer cells. Carcinogenesis 2013; 34: 1968–1975.
Chen Z, Zhang Y, Jia C, Wang Y, Lai P, Zhou X et al. mTORC1/2 targeted by n-3 polyunsaturated fatty acids in the prevention of mammary tumorigenesis and tumor progression. Oncogene 2014; 33: 4548–4557.
Cardaci S, Filomeni G, Ciriolo MR . Redox implications of AMPK-mediated signal transduction beyond energetic clues. J Cell Sci 2012; 125: 2115–2125.
Jung SN, Yang WK, Kim J, Kim HS, Kim EJ, Yun H et al. Reactive oxygen species stabilize hypoxia-inducible factor-1 alpha protein and stimulate transcriptional activity via AMP-activated protein kinase in DU145 human prostate cancer cells. Carcinogenesis 2008; 29: 713–721.
Else PL, Kraffe E . Docosahexaenoic and arachidonic acid peroxidation: It's a within molecule cascade. Biochim Biophys Acta 2015; 1848: 417–421.
Ding WQ, Lind SE . Phospholipid hydroperoxide glutathione peroxidase plays a role in protecting cancer cells from docosahexaenoic acid-induced cytotoxicity. Mol Cancer Ther 2007; 6: 1467–1474.
Seiler A, Schneider M, Forster H, Roth S, Wirth EK, Culmsee C et al. Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metab 2008; 8: 237–248.
Pierre AS, Minville-Walz M, Fevre C, Hichami A, Gresti J, Pichon L et al. Trans-10, cis-12 conjugated linoleic acid induced cell death in human colon cancer cells through reactive oxygen species-mediated ER stress. Biochim Biophys Acta 2013; 1831: 759–768.
Acknowledgements
The authors would like to thank the lipidomic plateform and the flow cytometry plateform facilities of Université de Bourgogne. The present work was supported by Ligue contre le cancer comité Grand-Est and by a French Government grant managed by the French National Research Agency under the program 'Investissements d’Avenir' with reference ANR-11-LABX-0021 (Lipstic Labex).
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Fluckiger, A., Dumont, A., Derangère, V. et al. Inhibition of colon cancer growth by docosahexaenoic acid involves autocrine production of TNFα. Oncogene 35, 4611–4622 (2016). https://doi.org/10.1038/onc.2015.523
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DOI: https://doi.org/10.1038/onc.2015.523
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