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THE CONTRIBUTION of K+ ION CHANNELS and the Ca2+-PERMEABLE TRPM8 CHANNEL to BREAST CANCER CELL PROLIFERATION

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THE CONTRIBUTION of K+ ION CHANNELS and the Ca2+-PERMEABLE TRPM8 CHANNEL to BREAST CANCER CELL PROLIFERATION THE CONTRIBUTION OF K+ ION CHANNELS AND THE Ca2+-PERMEABLE TRPM8 CHANNEL TO BREAST CANCER CELL PROLIFERATION. by Jeremy W Roy Submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy at Dalhousie University Halifax, Nova Scotia October 2010 © Copyright by Jeremy W Roy, 2010 DALHOUSIE UNIVERSITY DEPARTMENT OF PHYSIOLOGY AND BIOPHYSICS The undersigned hereby certify that they have read and recommend to the Faculty of Graduate Studies for acceptance a thesis entitled “THE CONTRIBUTION OF K+ ION CHANNELS AND THE Ca2+-PERMEABLE TRPM8 CHANNEL TO BREAST CANCER CELL PROLIFERATION” by Jeremy W Roy in partial fulfilment of the requirements for the degree of Doctor of Philosophy. Dated: October 26, 2010 Supervisor: _______________________________ Readers: _______________________________ _______________________________ _______________________________ ii DALHOUSIE UNIVERSITY DATE: October 26, 2010 AUTHOR: Jeremy W Roy TITLE: THE CONTRIBUTION OF K+ ION CHANNELS AND THE Ca2+- PERMEABLE TRPM8 CHANNEL TO BREAST CANCER CELL PROLIFERATION. DEPARTMENT OR SCHOOL: Department of Physiology and Biophysics DEGREE: PhD CONVOCATION: May YEAR: 2011 Permission is herewith granted to Dalhousie University to circulate and to have copied for non-commercial purposes, at its discretion, the above title upon the request of individuals or institutions. _______________________________ Signature of Author The author reserves other publication rights, and neither the thesis nor extensive extracts from it may be printed or otherwise reproduced without the author‟s written permission. The author attests that permission has been obtained for the use of any copyrighted material appearing in the thesis (other than the brief excerpts requiring only proper acknowledgement in scholarly writing), and that all such use is clearly acknowledged. iii For Dalhousie PhD Level Students iv TABLE OF CONTENTS LIST OF TABLES .............................................................................................................. ix LIST OF FIGURES ............................................................................................................. x ABSTRACT ........................................................................................................................ xii LIST OF ABBREVIATIONS AND SYMBOLS USED ................................................ xiii ACKNOWLEDGEMENTS ............................................................................................. xvi CHAPTER 1: INTRODUCTION ....................................................................................... 1 1.1 BREAST CANCER ............................................................................................... 1 1.2 MAMMARY GLAND STRUCTURE AND TRANSPORT PROPERTIES ........................................................................................................ 2 1.3 MALIGNANT TRANSFORMATION ................................................................ 5 1.4 CELL CYCLE ........................................................................................................ 8 1.5 ORIGIN, CLASSIFICATION AND MODELS OF BREAST CANCER .............................................................................................................. 10 1.6 ESTROGEN AND OTHER HORMONAL FACTORS................................... 12 1.7 ION CHANNELS AND CANCER ..................................................................... 18 1.7.1 K+ CHANNELS ............................................................................................. 20 1.7.2 Ca2+ PERMEABLE TRANSIENT RECEPTOR POTENTIAL CHANNELS ................................................................................................... 30 1.7.3 OTHERS ......................................................................................................... 36 1.8 HOW DO K+ CHANNELS CONTROL CELL PROLIFERATION? ............ 37 1.8.1 Ca2+ INFLUX ................................................................................................. 38 1.8.2 CELL VOLUME ........................................................................................... 40 1.8.3 INTRACELLULAR pH ................................................................................ 41 1.9 HOW DO OTHER ION CHANNELS CONTIBUTE TO CELL PROLIFERATION? ............................................................................................ 43 1.10 RATIONALE AND SPECIFIC AIMS OF THE THESIS ............................... 44 CHAPTER 2: MATERIALS AND METHODS ............................................................. 46 v 2.1 CELL CULTURE ................................................................................................ 46 2.2 SAMPLING .......................................................................................................... 47 2.3 DRUGS USED ...................................................................................................... 47 2.4 NOMENCLATURE ............................................................................................. 47 2.5 RNA EXTRACTION AND REVERSE TRANSCRIPTION (RT) ................. 48 2.6 POLYMERASE CHAIN REACTION (PCR) AND QUANTITATIVE PCR ....................................................................................................................... 48 2.7 WESTERN BLOTTING ..................................................................................... 51 2.8 [3H]-THYMIDINE INCORPORATION ........................................................... 52 2.9 CELL COUNTING .............................................................................................. 54 2.10 TRYPAN BLUE EXCLUSION ASSAY ............................................................ 54 2.11 COMPETITIVE LIGAND BINDING ASSAY ................................................. 54 2.12 45Ca2+ UPTAKE ASSAY ..................................................................................... 56 2.13 [3H]-THYMIDINE UPTAKE ............................................................................. 57 2.14 siRNA TRANSFECTION ................................................................................... 58 2.15 STATISTICAL ANALYSIS ............................................................................... 59 CHAPTER 3: RESULTS .................................................................................................. 60 3.1 MOLECULAR IDENTIFICATION OF K+ CHANNELS IN MCF-7 CELLS AND THEIR CONTRIBUTION TO CELL PROLIFERATION .............................................................................................. 60 3.2 REGULATION OF KCNH1 mRNA EXPRESSION BY E2. .......................... 62 3.3 KV10.1 AND KCa3.1 ACTIVITY IS IMPORTANT FOR BASAL CELL PROLIFERATION BUT NOT E2-STIMULATED PROLIFERATION .............................................................................................. 64 3.4 ER ANTAGONIST-SENSITIVE EFFECTS OF TRAM-34 ........................... 66 3.5 TRAM-34 MIMICS THE EFFECTS OF E2 ON GENE EXPRESSION IN MCF-7 CELLS ..................................................................... 68 3.6 DIRECT INTERACTION OF TRAM-34 WITH THE ER ............................. 69 3.7 KCa3.1, BUT NOT KV10.1 CHANNEL INHIBITION LEADS TO REDUCED BASAL 45Ca2+ INFLUX .................................................................. 71 vi 3.8 TRPM8 IS A Ca2+ INFLUX PATHWAY IN MCF-7 CELLS ......................... 73 3.9 BCTC AND ICILIN INHIBIT [3H]-THYMIDINE INCORPORATION ............................................................................................. 75 3.10 EFFECT OF TRPM8 MODULATION ON [3H]-THYMIDINE TRANSPORT ....................................................................................................... 76 3.11 TRPM8 CONTRIBUTES TO BASAL MCF-7 CELL PROLIFERATION .............................................................................................. 76 CHAPTER 4: DISCUSSION ............................................................................................ 80 4.1 K+ CHANNELS EXPRESSED IN MCF-7 CELLS .......................................... 81 4.1.1 K+ CHANNEL ACTIVITY AND MCF-7 CELL PROLIFERATION ....................................................................................... 84 4.1.2 E2 REGULATION OF KCNH1 mRNA EXPRESSION ........................... 87 4.1.3 KV10.1 and KCa3.1 CHANNEL ACTIVITIES ARE NOT CRITICAL FOR E2-STIMULATED CELL PROLIFERATION ........... 89 4.1.4 TRAM-34 IS A NOVEL ER AGONIST ...................................................... 92 4.2 HYPOTHESIZED K+ CHANNEL REGULATION OF CELL CYCLE MACHINERY ...................................................................................................... 94 4.3 TRPM8 CHANNELS IN MCF-7 CELLS ......................................................... 96 4.3.1 FUNCTIONAL IDENTIFICATION OF TRPM8 CHANNELS IN MCF-7 CELLS ............................................................................................... 97 4.3.2 BCTC AND ICILIN ARE NUCLEOSIDE TRANSPORT INHIBITORS ................................................................................................. 99 4.3.3 TRPM8 CHANNEL ACTIVITY CONTRIBUTES TO MCF-7 CELL PROLIFERATION .......................................................................... 101 4.4 KCa3.1, BUT NOT KV10.1 CHANNEL ACTIVITY REGULATES BASAL Ca2+ INFLUX ....................................................................................... 103 4.5 PROPOSED MODEL FOR THE CONTRIBUTION OF KV10.1, KCa3.1 AND TRPM8 CHANNELS TO MCF-7 CELL PROLIFERATION ...........................................................................................
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