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Characterization of Growth Hormone Signaling in the NCI60 Cancer Panel

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Characterization of Growth Hormone Signaling in the NCI60 Cancer Panel Characterization of Growth Hormone Signaling in the NCI60 Cancer Panel A dissertation presented to the faculty of the College of Arts and Sciences of Ohio University In partial fulfillment of the requirements for the degree Doctor of Philosophy Elahu Gosney Sustarsic August 2013 © 2013 Elahu Gosney Sustarsic. All Rights Reserved. 2 This dissertation titled Characterization of Growth Hormone Signaling in the NCI60 Cancer Panel by ELAHU GOSNEY SUSTARSIC has been approved for the Department of Biological Sciences and the College of Arts and Sciences by Xiaozhuo Chen Associate Professor of Microbiology Robert Frank Dean, College of Arts and Sciences 3 ABSTRACT SUSTARSIC, ELAHU GOSNEY, Ph.D., August 2013, Molecular and Cellular Biology Characterization of Growth Hormone Signaling in the NCI60 Cancer Panel Director of Dissertation: Xiaozhuo Chen Growth hormone Receptor (GHR) is a class I cytokine receptor. Under normal conditions, it is expressed in most tissues of the body.In addition to its presence in healthy tissue, GHR has been detected in cancer cells and tumors. There has been accumulating evidence that implicates GHR activation in carcinogenesis. Most research to date has focused on breast and prostate cancer, with a few studies in other cancer types. A limited number of studies have investigated a direct effect of GH on cancer cells, and even fewer have examined the mechanism of GH action in cancer cells. Our investigations began with a survey of gene expression in the 60 cell lines of the National Cancer Institute’s NCI60 panel. All of the metastatic melanoma lines examined show high expression of GHR. Five of the melanoma cell lines were treated with GH. In three of the cell lines, GH treatment increases cell growth. In one cell line, GH has a biphasic effect based on dose; a low dose moderately inhibits cell growth, while a high dose induces growth. Cell signaling pathways were analyzed as well. Some activation of mTOR was detected, along with strong STAT5 phosphorylation with GH treatment. A final group of studies examined the effect of GH treatment on cancer metabolism. In these experiments, we discovered a novel action of GH: an ability to increase the bioenergetic potential and potentiate the Warburg effect in cancer cells. These findings may have relevance to growth and invasion of metastatic melanoma cells in vivo. Further studies are warranted to determine if therapeutic interventions aimed at GH signaling might be beneficial in treatment of metastatic melanoma. 4 PREFACE ON DISSERTATION FORMAT This dissertation is divided into five chapters. The first one is an introduction to the current body of literature on the role GH may have in cancer. Chapters 2, 3 and 4 are in the form of manuscript drafts that will be submitted for publication in Endocrine-Related Cancer or a similar journal. Therefore, the formatting is set to the author guidelines for this journal. Importantly, in chapters 2-4, figures are not within the body of the text (as they are for chapters 1 and 5), but are shown at the end of each chapter. The final chapter lists the key findings and provides a roadmap of future research that should be undertaken as follow-up studies. 5 DEDICATION I dedicate this dissertation to the people who made it possible. To my mother, brother and sister for their nurturing love and support. Jahiah, your prescient advice to me many years ago put me on the path to this endeavor. Thanks to John for so many things, most importantly for giving me your passion for science. And to the love of my life, Riia. Without you, this would not have been possible. Minun rakkaus pupuni, sinä olet mailman ihana nainen. E<3R 6 ACKNOWLEDGMENTS I would like to acknowledge the many people who played a role in this project. Most importantly, Dr. John Kopchick, for bringing together several world experts who have assisted with this project. We owe a debt of gratitude to Dr. Steven Swanson, who suggested the use of the National Cancer Institute resources, specifically the NCI60 panel, for this investigation. Dr. Theresa Wood for offering her expertise in the insulin/IGF field, and Dr. Vincent Goffin for his encouragement and guidance in recombinant protein production and gene expression studies. Many thanks to everyone in the Kopchick lab who have been my friends, mentors and colleagues for many years, including Dr. Darlene Berryman, Dr. Edward List, Dr. Nick Okada and Dr. Bruce Kelder. Without the training, encouragement and guidance of these scientists, this work would not have been completed. Funding for the project was provided by the Diabetes Institute at Ohio University, the Molecular and Cellular Biology Program at Ohio University and the State of Ohio’s Eminent Scholars Program that includes a gift from Milton and Lawrence Goll. 7 TABLE OF CONTENTS Page Abstract ............................................................................................................................................ 3 Preface on Dissertation Format ........................................................................................................ 4 Dedication ........................................................................................................................................ 5 Acknowledgments............................................................................................................................ 6 List of Tables ................................................................................................................................. 11 List of Figures ................................................................................................................................ 12 Chapter 1: Introduction .................................................................................................................. 14 General overview .................................................................................................................... 14 GH background ....................................................................................................................... 19 The growth hormone gene family ..................................................................................... 19 Regulation of pituitary GH ............................................................................................... 20 GH activation of signaling via cell surface receptors ....................................................... 20 Signaling pathways affected by GH ................................................................................. 22 Endocrine GH Action: the somatomedin hypothesis ........................................................ 23 Autocrine/paracrine GH .................................................................................................... 25 GH and cancer literature review .............................................................................................. 26 Evidence from cell culture and human biopsies ............................................................... 26 Evidence from animal studies ........................................................................................... 36 Evidence from human studies (epidemiological and clinical) .......................................... 43 Contradictory data ............................................................................................................. 46 Summary ........................................................................................................................... 48 Comment on PRLR signaling and cancer ............................................................................... 50 Hypotheses and research objectives ........................................................................................ 51 Research approach ................................................................................................................... 52 Limitations of the study ........................................................................................................... 54 Value of the research ............................................................................................................... 55 Publication of data and dissertation outline ............................................................................. 55 References ............................................................................................................................... 57 Chapter 2: Expression of growth hormone, prolactin, and cognate receptors in the NCI60 cancer cell line panel ................................................................................................................................. 67 Abstract ................................................................................................................................... 67 Introduction ............................................................................................................................. 68 Materials and methods ............................................................................................................. 71 NCI60 cancer cell line RNA samples ............................................................................... 71 Real-time RT qPCR .......................................................................................................... 71 Primer design and validation ............................................................................................ 72 Human melanoma biopsy cDNA arrays ..........................................................................
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