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A Dissertation by A NR4A1 ANTAGONISTS TARGET THE ONCOGENIC PAX3-FOXO1A GENE AND INDUCE INTERLEUKIN -24 IN RHABDOMYOSARCOMA (RMS) A Dissertation by ALEXANDRA DIANNE LACEY Submitted to the Office of Graduate and Professional Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Chair of Committee, Stephen H. Safe Committee Members, Robert C. Burghardt Timothy D. Phillips Shannon Washburn Intercollegiate Faculty Chair, Ivan Rusyn August 2017 Major Subject: Toxicology Copyright 2017 Alexandra Lacey ABSTRACT Rhabdomyosarcoma (RMS) is a pediatric cancer for which common therapeutics include cytotoxic chemotherapeutics that result in adverse health outcomes later in adulthood. Previous studies have found NR4A1 expression contributes to the oncogenicity of several solid tumors and this study aims to determine if the established NR4A1-dependent mechanisms are observed in RMS. The orphan nuclear receptor NR4A1 is expressed in tumors from RMS patients and RMS cell lines. NR4A1 knockdown/antagonism also decreases the expression of growth promoting/pro-survival genes, inhibits mTOR signaling and induce oxidative stress. 1,1-Bis(3-indolyl)-1-(p-substituted phenyl)methane (C- DIM) analogs are NR4A1 ligands in RMS cells and inhibit RMS cell growth in vitro and in vivo. We also report overexpression of the nuclear receptor NR4A1 in rhabdomyosarcoma that is sufficient to drive high expression of the oncogenic PAX3-FOXO1A protein. RNAi for NR4A1 or C-DIM treatment decreased expression of PAX3-FOXO1A and its downstream effector genes. NR4A1 also regulated expression of β1-integrin, along with PAX3-FOXO1A, contributed to tumor cell migration that was blocked by C-DIM/NR4A1 antagonists. RNASeq studies using NR4A1 knockdown and antagonism and PAX3- FOXO1A antagonism in RMS cells revealed several genes that are commonly ii regulated by PAX3-FOXO1A and NR4A1, including the tumor suppressor-like factor interleukin-24 (IL-24). Studies show IL-24 expression is repressed in ARMS tumors and PAX3-FOXO1A positive tumors and transfection of ARMS cells with siPAX3-FOXO1A or siNR4A1, or treatment with C-DIM/NR4A1 antagonist result in IL-24 induction. In cells cotransfected with siPAX3-FOXO1A and siIL-24 or in IL-24 KO Rh30 cells, effects of siPAX3-FOXO1A were significantly abrogated. These data show that the oncogenic activity of PAX3- FOXO1A was due to, in part, IL-24 repression. Therefore, IL-24 induction contributes to the anti-carcinogenic actions observed upon PAX3-FOXO1A suppression. Previous studies have demonstrated the ability of C-DIMs to inhibit NR4A1-dependent pathways, yet these compounds exhibit low serum half-life, making them unsuitable for therapeutic applications. The current studies using selected p-hydroxyphenyl-substituted analogs (second-generation C-DIMs) show up to 10 times more potent than the parent compound in vitro and in vivo. This new class of potent NR4A1 antagonists is being developed for future clinical applications for treating RMS, a cancer which has a poor prognosis with current treatments. iii DEDICATION I would like to dedicate this thesis to my Father, Terry David Reeder, who passed away when I was a child, but continues to serve as an aspiration for the type of person I hope to become. I would not be where I am today if not for him. I also want to thank my mom Diane Reeder and my brother David Reeder. I also appreciate the support I have received from my in-laws as well as extended family. I would also like to thank my husband, Jason Lacey, for his continue love, support, patience, and laughs throughout this process. Your support and encouragement has pushed me to where I am today. iv ACKNOWLEDGEMENTS I would like to thank my committee chair, Dr. Stephen Safe, for all of his support and encouragement throughout my PhD program. I would also like to thank my committee members, Dr. Timothy Phillips, Dr. Robert Burghardt, Dr. Shannon Washburn, and Dr. Weston Porter for their guidance throughout the course of this research. Thanks also go to my friends and colleagues and the department faculty and staff for making my time at Texas A&M University a great experience. I would also like to acknowledge my husband, mom and brother, as well as my in- laws who have supported me throughout this time. Finally, thanks to former Safe Lab members, past and present: Former: Dr. Gayathri Chadalapaka, Dr. Sandeep Svreevalsan, Dr. Indira Jutooru, Dr. Vijayalekshmi Nair, and Dr. Yating Cheng. Current: Dr. Erik Hedrick, Dr. Xi Li, Dr. Un-Ho Jin, Keshav Karki, Dr. Jehoon Lee, Dr. Kumaravel Mohankumar, Lorna Safe, and Katherine Mooney. v CONTRIBUTORS AND FUNDING SOURCES Contributors This work was supported by a dissertation committee consisting of Drs. Stephen Safe and Shannon Washburn of the Department of Physiology and Pharmacology and Drs. Robert Burghardt and Timothy Phillips of the Department of Department of Veterinary Integrative Biosciences. Alexandra Lacey, Erik Hedrick, Xi Li, Ketan Patel, Ravi Doddapanneni, Mandip Singh, and Stephen Safe contributed to work presented in chapter II. Alexandra Lacey, Aline Rodrigues-Hoffman, and Stephen Safe contributed to work presented in chapter III. Alexandra Lacey, Erik Hedrick, Un-Ho Jin, Melanie Warren, and Stephen Safe contributed to work presented in chapter IV. Alexandra Lacey, Xi Li, Melanie Warren, and Stephen Safe contributed to work presented in chapter V. Funding Sources A Graduate Student Non-Teaching Assistantship from Texas A&M University Louis Stokes Alliance for Minority Participation supported research from 2013-2014. Graduate study from 2014-2017 was supported by a Diversity Fellowship from the College of Veterinary Medicine at Texas A&M University. vi TABLE OF CONTENTS Page ABSTRACT .................................................................................................. ii DEDICATION ............................................................................................... iv ACKNOWLEDGEMENTS ............................................................................. v CONTRIBUTORS AND FUNDING SOURCES ............................................ vi TABLE OF CONTENTS ............................................................................... vii LIST OF FIGURES ....................................................................................... ix CHAPTER I INTRODUCTION AND LITERATURE REVIEW ....................... 1 Cancer Overview………………………………………………………… 1 Rhabdomyosarcoma (RMS) Background……………………………... 16 Novel Drug Targets………………………………………………………. 26 Nuclear Receptors……………………………………………………….. 34 Orphan Nuclear Receptors……………………………………………… 60 NR4A Subfamily of Orphan Nuclear Receptors…………………….. .. 72 CHAPTER II NUCLEAR RECEPTOR 4A1 (NR4A1) AS A DRUG TARGET FOR TREATING RHABDOMYOSARCOMA (RMS) ... 89 Introduction ........................................................................................ 89 Materials and Methods ...................................................................... 91 Results ............................................................................................... 96 Discussion ......................................................................................... 108 CHAPTER III PAX3-FOXO1A EXPRESSION IS REGULATED BY THE NUCLEAR RECEPTOR NR4A1 IN RHABDOMYOSARCOMA AND CAN BE TARGETED BY NR4A1 ANTAGONISTS ................................. 114 vii Introduction ........................................................................................ 114 Materials and Methods ...................................................................... 116 Results ............................................................................................... 120 Discussion ......................................................................................... 132 CHAPTER IV ANTICANCER AGENTS DOWNREGULATE PAX3-FOXO1A IN ALVEOLAR RHABDOMYOSARCOMA (ARMS) CELLS AND INDUCE INTERLEUKIN-24 ............................................... 136 Introduction ........................................................................................ 136 Materials and Methods ...................................................................... 138 Results ............................................................................................... 143 Discussion ......................................................................................... 155 CHAPTER V POTENT BIS-INDOLE-DERIVED NUCLEAR RECEPTOR 4A1 (NR4A1) ANTAGONISTS INHIBIT RHABDOMYOSARCOMA (RMS) TUMOR GROWTH ...................................................................... 158 Introduction ........................................................................................ 158 Materials and Methods ...................................................................... 160 Results ............................................................................................... 163 Discussion ......................................................................................... 169 CHAPTER VI SUMMARY AND CONCLUSIONS ......................................... 173 REFERENCES ............................................................................................. 180 APPENDIX A ................................................................................................ 222 APPENDIX B ................................................................................................ 225 viii LIST OF FIGURES Page Figure 1: Cancer Hallmarks .......................................................................... 6 Figure 2: Children’s
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