title: Inflammation increases NOTCH1 activity via MMP9 and is counteracted by Eicosapentaenoic Acid-free fatty acid in colon cancer cells.
abstract: Aberrant NOTCH1 signalling is critically involved in multiple models of colorectal cancer (CRC) and a prominent role of NOTCH1 activity during inflammation has emerged. Epithelial to Mesenchymal Transition (EMT), a crucial event promoting malignant transformation, is regulated by inflammation and Metalloproteinase-9 (MMP9) plays an important role in this process. Eicosapentaenoic Acid (EPA), an omega-3 polyunsaturated fatty acid, was shown to prevent colonic tumors in different settings. We recently found that an extra-pure formulation of EPA as Free Fatty Acid (EPA-FFA) protects from colon cancer development in a mouse model of Colitis-Associated Cancer (CAC) through modulation of NOTCH1 signalling. In this study, we exposed colon cancer cells to an inflammatory stimulus represented by a cytokine-enriched Conditioned Medium (CM), obtained from THP1-differentiated macrophages. We found, for the first time, that CM strongly up-regulated NOTCH1 signalling and EMT markers, leading to increased invasiveness. Importantly, NOTCH1 signalling was dependent on MMP9 activity, upon CM exposure. We show that a non-cytotoxic pre-treatment with EPA-FFA antagonizes the effect of inflammation on NOTCH1 signalling, with reduction of MMP9 activity and invasiveness. In conclusion, our data suggest that, in CRC cells, inflammation induces NOTCH1 activity through MMP9 up-regulation and that this mechanism can be counteracted by EPA-FFA.
authors: Department of Surgical and Medical Sciences, University of Bologna, Bologna, Italy.|Center for Applied Biomedical Research (CRBA), S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors: Chiara
authors: C
authors: Fazio
authors: Department of Surgical and Medical Sciences, University of Bologna, Bologna, Italy.|Center for Applied Biomedical Research (CRBA), S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors: Giulia
authors: G
authors: Piazzi
authors: Department of Food Science, University of Naples "Federico II", Portici (NA), Italy.
authors: Paola
authors: P
authors: Vitaglione
authors: Food Quality & Design group, Wageningen University, Wageningen, The Netherlands.
authors: Vincenzo
authors: V
authors: Fogliano
authors: Department of Surgical and Medical Sciences, University of Bologna, Bologna, Italy.|Center for Applied Biomedical Research (CRBA), S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.|Endocrinology Unit S.Orsola-Malpighi Hospital, Bologna, Italy.
authors: Alessandra
authors: A
authors: Munarini
authors: Department of Surgical and Medical Sciences, University of Bologna, Bologna, Italy.|Center for Applied Biomedical Research (CRBA), S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors: Anna
authors: A
authors: Prossomariti
authors: Center for Applied Biomedical Research (CRBA), S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors: Maddalena
authors: M
authors: Milazzo
authors: Department of Surgical and Medical Sciences, University of Bologna, Bologna, Italy.|Center for Applied Biomedical Research (CRBA), S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors: Leonarda
authors: L
authors: D'Angelo
authors: Department of Surgical and Medical Sciences, University of Bologna, Bologna, Italy.|Center for Applied Biomedical Research (CRBA), S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors: Manuela
authors: M
authors: Napolitano
authors: Center for Applied Biomedical Research (CRBA), S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors: Pasquale
authors: P
authors: Chieco
authors: Gastroenterology Unit S.Orsola-Malpighi Hospital, Bologna, Italy.
authors: Andrea
authors: A
authors: Belluzzi
authors: Department of Surgical and Medical Sciences, University of Bologna, Bologna, Italy.
authors: Franco
authors: F
authors: Bazzoli
authors: Department of Surgical and Medical Sciences, University of Bologna, Bologna, Italy.|Center for Applied Biomedical Research (CRBA), S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors: Luigi
authors: L
authors: Ricciardiello
mesh_terms: D002454:Cell Differentiation; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005786:Gene Expression Regulation; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007249:Inflammation; D008070:Lipopolysaccharides / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; D008070:Lipopolysaccharides; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D015118:Eicosapentaenoic Acid; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate