Signaling and regulation of cysteinyl leukotriene receptors in intestinal epithelial cells and colon cancer Bengtsson, Astrid 2009 Link to publication Citation for published version (APA): Bengtsson, A. (2009). Signaling and regulation of cysteinyl leukotriene receptors in intestinal epithelial cells and colon cancer. Lund University. 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LUND UNIVERSITY PO Box 117 221 00 Lund +46 46-222 00 00 From the Department of Laboratory Medicine, Division of Cell Pathology, Lund University, Malmö, Sweden Signaling and regulation of cysteinyl leukotriene receptors in intestinal epithelial cells and colon cancer Astrid Bengtsson Academic dissertation By due permission of the Faculty of Medicine, Lund University, Sweden, to be publicly defended in the lecture hall, Clinical Research Center, Entrance 72, Malmö University Hospital (UMAS), Malmö on Friday, May 15, 2009, at 1 p.m. for the degree of Doctor of Philosophy, Faculty of Medicine Faculty opponent: Professor Maikel Peppelenbosch, Department of Cell Biology, University Medical Center Groningen, The Netherlands 1 To my family 3 © Astrid Bengtsson 2009 Department of Laboratory Medicine Lund University, Sweden Faculty of Medicine Doctoral Dissertation Series 2009:50 ISBN 978-91-86253-38-7 ISSN 1652-8220 Printed by Media-Tryck, Lund University, Sweden, 2009 4 TABLE OF CONTENTS Table of contents ................................................................................ 5 List of papers ...................................................................................... 7 Abbreviations ..................................................................................... 8 Introduction ..................................................................................... 11 Background ...................................................................................... 13 Anatomy of the intestines .............................................................. 13 The intestines under normal conditions ..................................... 13 Differentiation of colon epithelial cells ..................................... 13 The intestines under pathological conditions ................................ 15 Inflammatory bowel diseases .................................................... 15 The link between inflammation and cancer ............................... 17 How tumors arise and progress ..................................................... 19 Colorectal cancer ....................................................................... 21 Current treatment ....................................................................... 22 Classification of colorectal cancer ............................................. 23 The role of epidermal growth factor in cancer .......................... 23 The role of NF-țB in cancer ...................................................... 24 The role of AP-1 in cancer ........................................................ 26 Eicosanoids in inflammation and cancer ....................................... 28 Prostaglandin biosynthesis ........................................................ 28 Leukotriene biosynthesis ........................................................... 29 LTC4 synthase ........................................................................... 30 The cysteinyl leukotrienes and their receptors .......................... 30 CysLT1R .................................................................................... 31 CysLT2R .................................................................................... 32 5 Other cysteinyl leukotriene receptors ........................................ 33 The role of eicosanoids in cancer .............................................. 33 Eicosanoids with anti-inflammatory / anti-tumorigenic functions .................................................................................... 35 Antitumor agents and tumor suppression ...................................... 36 Interferons .................................................................................. 36 Type I interferons ...................................................................... 36 Interferon regulatory factors (IRFs) .......................................... 37 Retinoids .................................................................................... 37 Retinoic acid receptors (RARs) ................................................. 39 Transcription factors and cancer .................................................... 40 Transcriptional activation .......................................................... 42 Transcriptional repression ......................................................... 42 Present investigation ....................................................................... 43 Aim ................................................................................................ 43 Paper I ............................................................................................ 44 Background ................................................................................ 44 Results and discussion ............................................................... 44 Paper II .......................................................................................... 45 Background ................................................................................ 45 Results and discussion ............................................................... 46 Paper III ......................................................................................... 46 Background ................................................................................ 46 Results and discussion ............................................................... 47 Paper IV ......................................................................................... 48 Background ................................................................................ 48 Results and discussion ............................................................... 48 Concluding remarks and future perspectives ................................. 50 Populärvetenskaplig sammanfattning ........................................... 52 Acknowledgments ............................................................................ 54 References ........................................................................................ 57 6 LIST OF PAPERS This thesis is based on the following papers: I. Astrid M Bengtsson, Ramin Massoumi and Anita Sjölander. Leukotriene D4 induces AP-1 but not NFțB signaling in intestinal epithelial cells. Prostaglandins Other Lipid Mediat. 85 (2008):100-106. II. Cecilia Magnusson, Astrid M Bengtsson, Jian Liu, Roy Ehrnström, A. Yvonne Olsson Ceder and Anita Sjölander. EGF down-regulates the expression and functional response of the tumor-suppressing cysteinyl leukotriene 2 receptor in colon cancer cells. Submitted manuscript III. Astrid M Bengtsson, Cecilia Axelsson, Cecilia Magnusson, Gunilla Jönsson and Anita Sjölander. The cysteinyl leukotriene 2 receptor is involved in all-trans retinoic acid-induced differentiation of colon cancer cells. Manuscript IV. Yulyana Yudina, Ladan Parhamifar, Astrid M Bengtsson, Maria Juhas and Anita Sjölander. Regulation of the eicosanoid pathway by tumour necrosis factor alpha and leukotriene D4 in intestinal epithelial cells. Prostaglandins Leukot Essent Fatty Acids. 79 (2008):223-31. Reprints of paper I and IV were made with permission from the publisher. 7 ABBREVIATIONS AA Arachidonic acid AP-1 Activator protein 1 5-ASA 5-aminosalicylic acid APC Adenomatosis polyposis coli APL Acute promyelocytic leukemia ATRA All-trans retinoic acid Bcl-2 B-cell lymphoma 2 CDX2 Caudal-type homeobox 2 COX-2 Cyclooxygenase-2 cPLA2Į Cytosolic phospholipase A2Į CRBII Cellular retinol binding protein II CRC Colorectal cancer CRE cAMP-responsive element CREB cAMP-responsive element-binding protein CysLT Cysteinyl leukotriene CysLT1R Cysteinyl leukotriene receptor 1 CysLT2R Cysteinyl leukotriene receptor 2 DR Direct repeat E-box Enhancer box ECM Extracellular matrix EGF Epidermal growth factor EGFR Epidermal growth factor receptor EMT Epithelial to mesenchymal transition ERK1/2 Extracellular signal-regulated kinase 1 or 2 FAP Familial adenomatous polyposis FLAP 5-lipoxygenase activating protein 5-FU 5-fluorouracil GPCR G-protein coupled receptor HAT Histone acetyltransferases HDAC Histone deacetylase HIF Hypoxia-inducible factor 5-HPETE 5-hydroperoxyeicosatetraenoic acid 8 HUVEC Human umbilical vein endothelial cells IAP Intestinal alkaline phosphatase IBD Inflammatory