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Views on Life and Your Career Goals to Make Room for Someone You Never Knew You Could Love So Much

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Views on Life and Your Career Goals to Make Room for Someone You Never Knew You Could Love So Much Studies of Lipoxygenase Function Noel Patrick McCabe Medical College of Ohio 2004 DEDICATION This dissertation is dedicated to my loving wife Cari and my son Colin. Without Cari’s support, none of this would have been possible. Around a year and 8 months ago, we were blessed with a beautiful baby boy, Colin, and let me tell you life can become pretty complicated when you have to completely change your views on life and your career goals to make room for someone you never knew you could love so much. Having a little one can also lead to much unforeseen stress in one’s personal life, and I couldn’t mentally cope without Cari’s assistance. I also would like to thank my parents, James and Sharon McCabe, for everything they have done for me throughout my life. Without their guidance growing up and their openness with regards to what interested me, I couldn’t have become the man that I am today. You never realize how important it is to let a child do their own thing and discover the error of their ways until you are grown up and faced with a child of your own. ii ACKNOWLEDGEMENTS I would like to thank Dr. Jankun and Dr. Skrzyczak-Jankun. Without them, I never would have gotten to work on two very exciting, clinically relevant projects. Dr. Skrzyczak-Jankun provided the knowledge and know how of the X- ray crystallography work contained herein. X-ray analysis and data interpretation from such analysis was completed by her, first at the University of Toledo in the Instrumentation Center then at the Medical College of Ohio in the Department of Urology. Her knowledge of the field is remarkable. I also would like to thank Kanjing Zhou, not only was he instrumental in structural refinement, but he also provided some comedic relief by falling asleep periodically while wearing stereoscopic glasses. I would like to express my deepest gratitude to Dr. Steven Selman. Your enthusiasm for research for the sake of knowledge is refreshing. I have enjoyed our discussions on life, science, and career choices. Please look me up when you come to Cleveland. I would also like to thank you, as well as the other members of the lab, both permanent (Rick) and transient (Ranko and Kurt), for your friendship. iii TABLE OF CONTENTS List Page Title Page i Dedication ii Acknowledgements iii Table of Contents iv Introduction 1 Literature 9 Manuscript 1: “Platelet 12-Lipoxygenase Overexpression 64 by PC-3 Prostate Cancer Cells is Associated with Enhanced Production of Vascular Endothelial Growth Factor” Manuscript 2: “Curcumin inhibits lipoxygenase by binding 96 to its central cavity: theoretical and X-ray evidence” Manuscript 3: “Structure of curcumin in complex with 123 lipoxygenase and its relation to cancer” Discussion/Summary 152 Bibliography 158 Abstract 208 iv INTRODUCTION Prostate cancer is the second most common cause of cancer-related death among American men. Figures published by the American Cancer Society show the gravity and increasing incidence of this disease among North American males. Prostate cancer is the most common malignancy in males and the incidence of disease increases dramatically with age. Current methods of disease detection include the digital rectal exam and quantitation of serum prostate specific antigen (PSA). Prostate specific antigen has proven to be a very valuable indicator of prostate cancer. However, PSA testing lacks specificity, i.e., increased circulating PSA can result from multiple conditions such as benign prostate hyperplasia and prostatitis. While there is an inherent risk for all men to develop prostate cancer, chances of developing this disease can be influenced by multiple factors including, but not limited to, age, race and diet. It is believed that copious consumption of red meat and high-fat dairy foods, thus increasing the amount of animal fats ingested, can increase the chances of developing prostate cancer. Early animal studies on tumorigenesis provide the first link that specific dietary polyunsaturated fatty acids promote cancer development (Broitman 1977). Later work determined that these polyunsaturated fatty acids must be metabolized to their oxygenated products to augment tumorigenesis (Bull et al. 1984; Setty et al. 1987; Glasgow et al. 1992). One such fatty acid, arachidonic acid, is an essential fatty acid obtained either through diet or by enzymatic 1 conversion of other fatty acids. Enzymatic oxidation of arachidonic acid occurs through several families of enzymes: cycloxygenases, lipoxygenases, and cytochrome P450 oxygenases. Metabolism of arachidonic acid by any of these groups of enzymes results in the generation of eicosanoids. Eicosanoids derived from arachidonic acid metabolism are known to play significant roles in a multitude of physiological and pathological conditions. The majority of research effort is dedicated to conditions related to the production of prostaglandins and other cyclooxygenase metabolites. However, considerable data have accumulated implicating the importance of lipoxygenase products of arachidonic acid in the initiation and progression of numerous pathological disorders, most notably cancer. Hamberg and Samuelson (1974) were the first to show that a lipoxygenase was present in human platelets and was capable of metabolizing arachidonic acid, resulting in the production of 12(S)-hydroxy-5,8,10,14- eicosatetraenoic acid (12(S)-HETE). This lipoxygenase was capable of inserting oxygen at carbon 12 in arachidonic acid, therefore, it was dubbed platelet-type 12-lipoxygenase (P12-LOX). This was the first documented case concerning the existence of lipoxygenases in animals. It wasn’t until 1990 that P12-LOX expression was shown in human erythrolukemia cells (HEL) (Funk et al. 1990) disproving the belief that this enzyme was specific to platelets. Shortly thereafter, it was shown that P12-LOX was expressed in various tumor tissues and cells including human epidermoid carcinoma A431 (Chang, Liu et al. 1993), 2 Lewis lung 3LL, B16a melanoma (Chen et al. 1994) and prostate (Gao et al. 1995). Gao et al. (1995) found that P12-LOX mRNA expression was significantly higher in prostate adenocarcinoma tissue compared to matched normal prostate epithelium, and that this increased expression correlated with advanced stage and grade adenocarcinoma. In this pivotal study, tissue from over 130 patients were examined with 38% demonstrating elevated P12-LOX mRNA in cancerous tissue compared to normal matched tissue. The level of elevation of P12-LOX gene expression among high grade prostatic adenocarcinomas compared to that of low and intermediate proved to be statistically significant. This study suggested an association between prostate cancer progression and elevated expression of P12-LOX. Because of this early work, the significance of P12-LOX in prostate cancer became of utmost interest. Prostate cancer progression, as with other forms of cancer, is dependent upon a process called angiogenesis (Folkman et al. 1989). Angiogenesis, or extension of existing vasculature, is a complex process which depends upon the production and release, in this case from tumor cells, of angiogenic proteins such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), as well as specific arachidonate derived eicosanoids (Nie et al. 2000b). The expression of VEGF in prostate cancer has been shown to be dependent, at least initially, upon the presence of androgen (Joseph and Isaacs 1997; Stewart et al. 2001). Treatment of prostate carcinoma by androgen deprivation, thus effectively reducing VEGF production, will ultimately lead to tumor regression 3 (Moon et al. 1997). This effect is due at least in part by limiting the expansion of tumor induced vascularization. Unfortunately, prostate tumor resurgence can occur as a result of androgen independent tumor cell propagation and recommencement of the angiogenic process. Platelet 12-LOX is believed to play multiple roles in the progression of prostate cancer, in part by promotion of angiogenesis. Expression of P12-LOX has been confirmed in multiple prostate cancer cell lines including PC-3, DU145, and LnCAP (Timar et al. 2000). Stable overexpression of P12-LOX in PC-3 cells was able to promote accelerated growth following subcutaneous injection of nude mice, a condition resulting from increased tumor vascularization (Nie et al. 1998). Overexpression of P12-LOX also leads to constitutive activation of the transcription factor NF-κB (Kandouz et al. 2003), a factor previously linked to induction of the angiogenic protein VEGF (Huang et al. 2000). Lipoxygenase activity can also lead to the production of reactive oxygen species (Roy et al. 1994), which can in turn lead to an increase in VEGF gene expression (Kuroki et al. 1996). More definitively, augmentation of VEGF expression has been shown to occur in human smooth vascular muscle cells following exposure to 12(S)- HETE (Natarajan et al. 1997a). Vascular endothelial growth factor mRNA is increased in prostate tumors compared to normal prostate tissue, and VEGF inhibition suppresses primary prostatic tumor growth and metastasis (Kirschenbaum et al. 1997; Melnyk et al. 1999). In addition, VEGF expression levels are increased in prostate cancer cells of higher metastatic potential (Ferrer et al. 1997; Jackson et al. 1997) and this can be attributed to an increased ability 4 of these cells to stimulate angiogenesis, thus providing access to the circulatory system for tumor dissemination. The metastatic cascade (reviewed in Dailey and Imming 1999) consists of intricate interdependent steps which rely on the presence of local vasculature, as discussed above. By a process dubbed intravasation, tumor cells gain access to the blood stream and traverse to secondary locations within the body. Upon arriving at a distant site, tumor cells exit the vasculature, a process known as extravasation, by inducing vascular endothelial cell retraction, promote dissolution of the basement membrane, and invade local tissue. Each step in the metastatic process is regulated by various growth factors, cytokines and bioactive lipid derivatives of arachidonic acid. Multiple steps of the metastatic process are modulated by 12(S)-HETE and a review of 12(S)-HETE’s involvement has recently been written (Honn et al.
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