title: Inhibition of colon cancer growth by docosahexaenoic acid involves autocrine production of TNFα.
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.
authors: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 866, Dijon, France.|UFR Sciences de la Vie, Terre et Environnement, Université de Bourgogne, Dijon, France.
authors: A
authors: A
authors: Fluckiger
authors: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 866, Dijon, France.|UFR Sciences de la Vie, Terre et Environnement, Université de Bourgogne, Dijon, France.
authors: A
authors: A
authors: Dumont
authors: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 866, Dijon, France.|UFR des sciences de santé, Université de Bourgogne, Dijon, France.
authors: V
authors: V
authors: Derangère
authors: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 866, Dijon, France.|Centre Georges François Leclerc, Dijon, France.
authors: C
authors: C
authors: Rébé
authors: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 866, Dijon, France.|UFR Sciences de la Vie, Terre et Environnement, Université de Bourgogne, Dijon, France.
authors: C
authors: C
authors: de Rosny
authors: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 866, Dijon, France.|UFR des sciences de santé, Université de Bourgogne, Dijon, France.
authors: S
authors: S
authors: Causse
authors: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 866, Dijon, France.|UFR Sciences de la Vie, Terre et Environnement, Université de Bourgogne, Dijon, France.
authors: C
authors: C
authors: Thomas
authors: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 866, Dijon, France.|UFR des sciences de santé, Université de Bourgogne, Dijon, France.|Centre Georges François Leclerc, Dijon, France.
authors: L
authors: 0000-0002-2774-438X
authors: L
authors: Apetoh
authors: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 866, Dijon, France.|UFR Sciences de la Vie, Terre et Environnement, Université de Bourgogne, Dijon, France.
authors: A
authors: A
authors: Hichami
authors: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 866, Dijon, France.|UFR des sciences de santé, Université de Bourgogne, Dijon, France.|Centre Georges François Leclerc, Dijon, France.
authors: F
authors: F
authors: Ghiringhelli
authors: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 866, Dijon, France.|UFR Sciences de la Vie, Terre et Environnement, Université de Bourgogne, Dijon, France.
authors: M
authors: M
authors: Rialland
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019898:Autocrine Communication; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004281:Docosahexaenoic Acids / Q000008:administration & dosage*; D000071316:Forkhead Box Protein O3 / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D023041:Xenograft Model Antitumor Assays
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D014409:Tumor Necrosis Factor-alpha; D004281:Docosahexaenoic Acids