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Studies of Protein S-Nitrosylation in Prostate Cancer Focused on Integrin Alpha 6, Proliferating Cell Nuclear Antigen and Estrogen Receptor Beta

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Studies of Protein S-Nitrosylation in Prostate Cancer Focused on Integrin Alpha 6, Proliferating Cell Nuclear Antigen and Estrogen Receptor Beta Studies of Protein S-nitrosylation in Prostate Cancer focused on Integrin Alpha 6, Proliferating Cell Nuclear Antigen and Estrogen Receptor Beta By Jared Isaac, B.Sc. Biochemistry, Lee University, Cleveland, TN 2005 For partial requirement of Doctorate of Philosophy in Biomedical Research degree from the University of Cincinnati College of Medicine Thesis Committee: Shuk-Mei Ho, PhD; Thesis Advisor Robert Brackenbury, PhD; Thesis Committee Chair Susan Waltz, PhD Shao-Chun Wang, PhD Ying-Wai Lam, PhD i ABSTRACT Prostate cancer is the second most common cancer and cause of cancer related death of men in the United States of America. Given the proportion of men who will be entering the fifth decade, the number of prostate cancer cases will only increase in the next 10-20 years. Therefore, it is imperative to understand and develop treatment for prostate cancer. Prostate cancers typically have the accumulation of free radicals such as reactive oxygen and nitrogen species. These free radicals can damage the cell and alter its normal cellular processes. The purpose of this body of work is to understand the affect of one free radical, nitric oxide (NO) and how it affects the function of proteins by post- translationally modifying them in a process called S-nitrosylation. Chapter 1 gives a brief background on the prostate’s function in the reproductive system, diseases that affect the prostate, prostate cancer, the role of reactive nitrogen species in the prostate, S-nitrosylation, and a mass spectrometry based profiling study identifying S-nitrosylated proteins in the normal prostate epithelial cells. Chapter 2 focuses on integrin alpha 6, ITGα6, which becomes S-nitrosylated after exposure to iNOS. This chapter shows how S-nitrosylation of ITGα6 cysteine 86 by iNOS increases ITGα6 mediated prostate cancer cell migration by increasing its heterodimerization with ITGβ1 and decreasing its adhesion to laminin-β1 chain. Chapter 3 examines another identified S-nitrosylated protein, proliferating cell nuclear antigen, PCNA in prostate cancer. Doxorubicin causes PCNA S-nitrosylation in prostate cancer cells by ii upregulating iNOS. When PCNA cysteine 81 becomes S-nitrosylated this causes PCNA to bind to the chromatin and arrest DNA synthesis. Chapter 4 is preliminary work in which estrogen receptor beta is shown to be S-nitrosylated in androgen independent cells after treatment with estrogen. Cysteines 108, 209, and 512 were identified to be S- nitrosylated by mass spectrometry and iNOS expression inhibits expression of an ERβ regulated gene, vitellogenin. Chapter 5 summarizes the results, limitations, future directions and discusses the prospect of preventing S-nitrosylation in the treatment of prostate cancer. This thesis shows for the first time how elevated levels of nitric oxide affect protein function by S-nitrosylation in the background of prostate cancer. The data presented here show that with different stimuli, three proteins important for prostate cancer progression, ITGα6, PCNA and ERβ can all become S-nitrosylated. ITGα6 S- nitrosylation lends support to similar studies by showing S-nitrosylation promotes prostate cancer progression by increasing prostate cell migration which has clear implications in prostate cancer metastasis. However, future experiments are needed to conclusively determine whether S-nitrosylation promotes or inhibits PCNA and ERβ function in prostate cancer. Animal studies and staining of patient biopsies are preferred before the development of potential clinical treatments modulating cellular S- nitrosylation. In conclusion, reducing the level of S-nitrosylation remains a potentially attractive target for the treatment of advanced stage prostate cancer. iii iv ACKNOWLEDGEMENTS Thesis Mentor Dr. Shuk-Mei Ho: Thank you for molding me into the scientist that I am today. I am truly thankful for the opportunity to learn all the techniques that were available in the lab and the freedom to pursue my research project in S-nitrosylation. The high standard you held me to taught me to reach my potential. You have molded my scientific thinking and training and I will take the lessons that I have learned with me forward in life. I will always remember my time in your lab fondly, and will miss the discussions, lunch-time parties, and lab meetings. I have been fortunate to have you to facilitate my experiment planning, troubleshooting, networking and access to resources in the department and across the university. In the beginning you warned me that my thesis project was high- risk/high-gain, but in retrospect, it was the best choice for me to develop my critical thinking skills to become an independent investigator. You have always been extremely supportive of new directions as long as I can defend my rationale. Aside from my bench work, you developed my professionalism. My first test was to pass my PhD qualifying exam. This was a significant hurdle for me and you supported me through each step. Not long afterwards, I was awarded a departmental NIEHS pre-doctoral training award. During this time, you encouraged me to think critically and apply for my own grant funding through outside funding agencies. My crowning achievement was being awarded my own funding which would not have happened without your support and encouragement. I owe my maturation as a young v scientist to you, and for that I am thankful. As your student I have had extraordinary opportunities, allowing me to brush shoulders with leaders in biomedical research as well as to learn the latest techniques. In retrospect, the opportunities in your lab were tremendous. With my extensive training and specialization in proteomics and cell biology from Dr. Shuk-Mei Ho, I believe I am well prepared for my future career in science. I am grateful for the opportunity to pursue my doctoral thesis research under your guidance with your extensive experience in prostatic diseases. Thesis Committee Chair Dr. Robert Brackenbury: Your expertise in cell-cell interactions in normal development and invasion of tumor cells has definitely been invaluable in my studies in cell migration in the ITGα6 S- nitrosylation project. You were one of the reasons I chose the Cancer and Cell Biology program because of your enthusiasm for the program and biomedical research in general. You have been one of the best teachers I have ever had and I enjoyed the classes that you taught at UC. You have been very encouraging and supportive throughout my thesis study in the classroom as well as serving as my thesis committee chair. Thesis Committee Members Dr. Susan Waltz: Your expertise with endocrine related cancers provided a different prospective to my studies in protein S-nitrosylation in prostate cancer. Your expertise in tumor vi formation and metastasis has been invaluable. Your planning and advice skills have provided clear solutions when problems, roadblocks and dead-ends were encountered. Thank you for your support in the thesis committee meetings as well as being my co- mentor for my training grant. Dr. Shao-Chun Wang: I thank you for being approachable and available to discuss my data for the ITGα6 and PCNA papers. Your honesty, helpfulness, and expertise of PCNA phosphorylation have been invaluable for my studies of PCNA S-nitrosylation. I have great respect for your accomplishments and your research is a model for my future scientific endeavors. Dr. Ying Wai Lam: Thank you for taking the time to teach me as your colleague. The highlights of my time at UC were definitely our conversations and working closely with you in the lab until late hours of the night. Thank you for showing me the importance of hard work, time management and literature review. I cannot express how thankful I am that you took the time to teach me mass spectrometry, the biotin switch technique and HPLC. Your example of diligence and perseverance will lead me during my scientific career. vii Professors, Post-docs and Students Dr. Pheruza Tarapore: I thank you for your willingness to help with my research. I value your input and ideas for experiments. It is because of your shared ideas that the S-nitrosylation functional study papers are a reality. Your enthusiasm for research and critical thinking inspire my own motivation in the lab. In my future position, I will remember what you have shown me about cell biology, immunofluoresence, microscopy and scientific writing. Dr. Jarek Meller, your expertise using bioinformatic analysis has been invaluable to predict functional aberrations of proteins induced by S-nitrosylation. Dr. Xiang Zhang, thank you for your insights and discussion of how I should mutate ITGα6 and your mutation of PCNA. Dr. Ricky Leung, thank you for sharing your expertise of ERβ functional assays to determine the role ERβ S-nitrosylation. Dr. Neville Tam and Saikumar Karyala, M. Sc., thank you for your input and suggestions to better develop my projects. Dr. Ming Lam, thank you for providing your reagents and experience of lentiviral production and cell migration and invasion assays. Ming-Tsung Lee, M. Sc., thank you for your discussions and sharing your experience and reagents. I am especially thankful for you conducting the ERβ transactivation assays. Dr. Yong Yuan, thank you for sharing your experimental parameters of how you identified the S-nitrosylation sites of ERβ. viii Cancer and Cell Biology and Biomedical Flex Programs I thank the Biomedical Flex program for allowing me the opportunity to pick my lab rotations from every available lab and supporting me until choosing the Cancer and Cell Biology program. I am thankful to the Cancer and Cell Biology program for my support and fostering an environment of scientific comradery. Funding Agencies I am indebted to the following U.S. agencies that provided my salary to carry out the studies outlined in this dissertation through the following training grants: National Institute of Environmental Health Sciences Pre-doctoral training grant. Army Department of Defense Congressionally Directed Medical Research Program predoctoral training grant.
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