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Mhopkins Dissertation CHARACTERIZATION OF THE EFFECTS OF FREE FATTY ACID RECEPTOR 4 (FFA4) AGONISTS ON HUMAN CANCER CELLS By MANDI MARIE HOPKINS A dissertation submitted in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY WASHINGTON STATE UNIVERSITY College of Pharmacy MAY 2015 © Copyright by MANDI MARIE HOPKINS, 2015 All Rights Reserved © Copyright by MANDI MARIE HOPKINS, 2015 All Rights Reserved To the Faculty of Washington State University: The members of the Committee appointed to examine the dissertation of MANDI MARIE HOPKINS find it satisfactory and recommend that it be accepted. Kathryn E. Meier, Ph.D., Chair Clifford E. Berkman, Ph.D. David X. Liu, Ph.D. Susan A. Marsh, Ph.D. ii ACKNOWLEDGEMENTS My thanks to my labmates over the years, Stella Feng, Mengwei Liu, and Ze Liu, who have taught me a lot, and not just about science. Also, thank you to my committee members, both past and present, for your guidance. I really appreciate all the work you have put in helping me to be successful in graduate school. I especially want to thank my mentor, Dr. Kay Meier, for all of your support and guidance. Thank you also to my family members, especially Mom and Dad, and my friends; I couldn’t have done it without your support. iii CHARACTERIZATION OF THE EFFECTS OF FREE FATTY ACID RECEPTOR 4 (FFA4) AGONISTS ON HUMAN CANCER CELLS Abstract by Mandi Marie Hopkins, Ph.D. Washington State University May 2015 Chair: Kathryn E. Meier Dietary omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have many beneficial effects on human health. These include promising inhibitory effects on cancer cell growth and invasion. The goal of this project was to delineate the mechanisms involved in this inhibitory effect. Omega-3 fatty acids act via several potential molecular mechanisms that include their action as agonists at free fatty acid receptors (FFARs), which are G protein- coupled receptors. In this project, we show that two FFARs activated by omega-3 fatty acids, FFA1 and FFA4 (formerly GPR120), are expressed in the human prostate cancer cell lines DU145 and PC-3. EPA completely inhibits lysophosphatidic acid (LPA)- and epidermal growth factor (EGF)-mediated proliferation and migration in prostate cancer cells. TUG-891, a synthetic and highly selective FFA4 agonist, mimics the inhibitory effects of EPA. The inhibitory effects are readily reversed upon removal of TUG-891 or EPA. Knockdown of FFA4, iv through the utilization of silencing RNA, abolished the effects of both EPA and TUG- 891 in these cells. Positive cross-talk has been shown to occur between LPA receptors and EGF receptors. We therefore hypothesized that FFA4 inhibits the LPA receptor LPA1, via β-arrestin-2, to inhibit EGF-induced proliferation and migration. Consistent with this hypothesis, when LPA1 is knocked down, FFA4 agonists no longer inhibit EGF-induced proliferation and migration. In addition, we found that β-arrestin-2 is essential for both LPA- and EGF-mediated signaling in prostate cancer cells. The inhibitory effects of FFAR agonists were also explored in two human breast cancer cell lines, MCF-7 and MDA-MB-231. The results suggest that FFA1, not FFA4, is more likely to be responsible for the inhibitory effects of omega-3 fatty acids in these cells. The results of these studies establish that there are specific receptor(s) responsible for mediating the effects of omega-3 fatty acids on human cancer cells. This finding will facilitate the development of targeted pharmaceutical therapies for prevention and treatment of prostate and breast cancer. These results show for the first time the importance of the FFAR family as receptors for omega-3 fatty acids in human cancer cells. v TABLE OF CONTENTS Page ACKNOWLEDGEMENTS ................................................................................................... iii ABSTRACT .........................................................................................................................iv LIST OF TABLES.................................................................................................................x LIST OF FIGURES..............................................................................................................xi CHAPTER 1: INTRODUCTION........................................................................................... 1 1.1 PROSTATE CANCER................................................................................................. 1 1.1.1 BENEFITS OF A HIGHER N-3/N-6 FA RATIO .................................................... 2 1.2 FATTY ACIDS............................................................................................................. 3 1.2.1 OMEGA-6 FATTY ACIDS .................................................................................... 4 1.2.2 OMEGA-3 FATTY ACIDS .................................................................................... 5 1.3 OMEGA-3 FATTY ACIDS AND PROSTATE CANCER .............................................. 8 1.3.1 IN VITRO STUDIES ............................................................................................. 9 1.3.2 IN VIVO STUDIES.............................................................................................. 10 1.3.3 HUMAN EPIDEMIOLOGICAL STUDIES ........................................................... 11 1.4 G PROTEIN-COUPLED RECEPTORS..................................................................... 15 1.4.1 GPCR CLASSIFICATION .................................................................................. 16 1.4.2 G PROTEIN-MEDIATED SIGNALING ............................................................... 17 1.4.3 G PROTEIN SIGNALING PATHWAYS.............................................................. 19 1.4.4 ARRESTINS....................................................................................................... 20 1.4.5 ARRESTIN-MEDIATED SIGNALING................................................................. 21 1.4.6 LYSOPHOSPHATIDIC ACID ............................................................................. 23 1.4.7 LPA CROSS-TALK WITH EGFR ....................................................................... 24 1.5 GENERAL ASPECTS OF RECEPTOR CROSS-TALK ............................................ 25 vi 1.6 FREE FATTY ACID RECEPTOR FAMILY................................................................ 27 1.6.1 FFA1-3 ............................................................................................................... 28 1.7 FFA4.......................................................................................................................... 30 1.7.1 SYNTHETIC FFA4 AGONISTS.......................................................................... 32 1.71.2 FFA4 AND CANCER........................................................................................ 34 1.8 GAPS IN KNOWLEDGE AND HYPOTHESIS........................................................... 34 CHAPTER 2: MATERIALS AND METHODS .................................................................... 37 2.1 MATERIALS.............................................................................................................. 37 2.1.1 REAGENTS........................................................................................................ 37 2.1.2 ANTIBODIES...................................................................................................... 38 2.2 METHODS ................................................................................................................ 38 2.2.1 CELL CULTURE ................................................................................................ 38 2.2.2 CELL PROLIFERATION ASSAYS..................................................................... 39 2.2.3 CELL MIGRATION ASSAYS.............................................................................. 39 2.2.4 RT-PCR.............................................................................................................. 40 2.2.5 CELL INCUBATIONS FOR SIGNAL TRANSDUCTION ASSAYS..................... 41 2.2.6 IMMUNOBLOTTING .......................................................................................... 41 2.2.7 RNA INTERFERENCE....................................................................................... 42 2.2.8 STATISTICAL ANALYSIS.................................................................................. 43 CHAPTER 3: EFFECTS OF FFA4 AGONIST-INDUCED INHIBITION OF PROSTATE CANCER CELL SIGNALING............................................................................................. 44 3.1 INTRODUCTION....................................................................................................... 44 3.2 RESULTS.................................................................................................................. 45 3.2.1 FFAR EXPRESSION IN HUMAN PROSTATE CANCER CELLS...................... 46 3.2.2 EFFECTS OF FFAR AGONISTS ON HUMAN PROSTATE CANCER CELL vii PROLIFERATION ....................................................................................................... 46 3.2.3 EFFECTS OF FFA4 AGONISTS ON HUMAN PROSTATE CANCER CELL MIGRATION .............................................................................................................. 57 3.2.4 EFFECTS OF FFA4 KNOCKDOWN ON HUMAN PROSTATE CANCER CELL PROLIFERATION AND MIGRATION ....................................................................... 57 3.3 DISCUSSION...........................................................................................................
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