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Copyright by Luke Yun-Kong Koong 2014 The Dissertation Committee for Luke Yun-Kong Koong Certifies that this is the approved version of the following dissertation: THE DIRECT EFFECTS OF ESTRADIOL AND SEVERAL XENOESTROGENS ON CELL NUMBERS OF EARLY- VS. LATE- STAGE PROSTATE CANCER CELLS Committee: Cheryl S Watson, PhD, Mentor Darren Boehning, PhD, Chair Gracie Vargas, PhD Randall M Goldblum, MD Nancy Ing, DVM, PhD _______________________________ Dean, Graduate School THE DIRECT EFFECTS OF ESTRADIOL AND SEVERAL XENOESTROGENS ON CELL NUMBERS OF EARLY- VS. LATE- STAGE PROSTATE CANCER CELLS by Luke Yun-Kong Koong, BS Dissertation Presented to the Faculty of the Graduate School of The University of Texas Medical Branch in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy The University of Texas Medical Branch December, 2014 Dedication This dissertation is dedicated to my family, whom has supported me with love and encouragement throughout my life; my friends, who push me to greater heights; and most importantly God, who continues to bless me every day with life and joy. Acknowledgements I would like to acknowledge my mentor, Cheryl S Watson, who has guided me through my graduate work. She has shown me how to be a true scientist and a responsible steward of our environment. I am forever grateful for the avenues she has opened up for my life and career. Additionally, I would like to thank my committee members for all of their constructive ideas throughout my project, as well as encouragement along the way. Another key figure in my graduate career is Jennifer Jeng of the Watson laboratory, who helped teach me many of the assays used in this study, and who was also available for advice and suggestions. The National Institutes of Environmental Health Sciences (NIEHS) Environmental Toxicology Training Grant helped me acquire numerous skills toward my career, as well as monetary support, and for that I am truly grateful. Finally, I want to acknowledge the GSBS and the support they provided me in finishing my degree. This work was supported by the NIEHS T32ES007254 Environmental Toxicology Training Grant. iv THE DIRECT EFFECTS OF ESTRADIOL AND SEVERAL XENOESTROGENS ON CELL NUMBERS OF EARLY- VS. LATE- STAGE PROSTATE CANCER CELLS Publication No._____________ Luke Yun-Kong Koong, PhD The University of Texas Medical Branch, 2014 Supervisor: Cheryl S Watson Prostate cancer is the most common non-cutaneous cancer among men, and diethylstilbestrol (DES) is an estrogen that has been used clinically to combat advanced tumors. Estrogens can indirectly decrease androgen production by central negative feedback inhibition, but may also have direct tumor killing mechanisms by a less well understood mechanism. To elucidate these mechanisms and provide understanding for potential future therapies, we identified cellular pathways and rapid signaling events that act via estrogen receptors (ERs) and contribute to estradiol (E2) or DES-mediated cell killing/growth arrest. E2 was much more effective than DES at reducing cell numbers of both LAPC-4 early-stage androgen-dependent and PC-3 late-stage androgen-independent prostate cancer cells. Both E2 and DES rapidly (within minutes) activated mitogen- activated protein kinases, generated reactive oxygen species (ROS), induced apoptosis and necroptosis, and regulated the activation and levels of cell cycle proteins. Regulation of cyclin D1 played a major role in blocking cell proliferation, but extracellular signal- v regulated kinase (ERK) causing ROS generation, phosphorylation of p38, apoptosis, and phosphorylation of p16INK4A also contributed. Our rapid effects suggested the participation of membrane ERs (mERs). ERα and β mediated E2’s ability to increase ROS through sustained ERK activation, and increased p-cyclin D1 levels in LAPC-4 cells. However, ERβ and GPR30 mediated these responses in PC-3 cells. Apoptosis was initiated in LAPC-4 and PC-3 cells by E2 only, and not by DES. Necroptosis was not altered by estrogens in either cell line. We showed for the first time the presence of mERs in both early and late prostate cancer cells. Then several xenoestrogens (XEs) were evaluated for their ability to increase or decrease prostate cancer cell numbers. Coumesterol and genistein unexpectedly stimulated prostate cancer cell growth, while resveratrol minimally increased cell numbers in both early and late-stage cells. Bisphenol A (BPA) slightly, though significantly, increased cell numbers in LAPC-4 cells only. Again, control of cyclin D1 protein levels was a key mediator of the growth change effects. The findings of these studies should be relevant to the clinical treatment of prostate tumors, including development of ER subtype-specific agents to control proliferation and cell death signaling pathways. Our findings regarding XEs should help establish guidelines for prostate cancer patients regarding consumption of safe dietary concentrations of phytoestrogens and acceptable exposure levels to BPA. vi TABLE OF CONTENTS List of Tables .............................................................................................................ix List of Figures ............................................................................................................x List of Abbreviations .................................................................................................xiii Chapter 1: Introduction ..............................................................................................15 Prostate tumors and methods of treatment ........................................................15 Prostate function and anatomy ..........................................................................17 Prostate cancer treatment regimens ..................................................................22 Development of androgen-independent tumors ................................................24 Estrogens and estrogen receptor physiology ....................................................27 Roles of membrane estrogen receptors in nongenomic responses ...................31 Estrogen receptor control of cell proliferation or death ....................................33 Estrogen receptors in the prostate and prostatic disease ...................................34 Xenoestrogens and effects on living systems ...................................................35 Aims of studies in this dissertation ...................................................................37 Aim 1 .......................................................................................................37 Aim 2 .......................................................................................................38 Chapter 2: Direct estradiol and diethylstilbestrol actions on early- vs. late-stage prostate cancer cells ..........................................................................................39 Abstract .............................................................................................................39 Introduction .......................................................................................................40 Materials and Methods......................................................................................43 Results ...............................................................................................................46 Discussion .........................................................................................................58 Conclusions .......................................................................................................63 Chapter 3: Rapid, nongenomic signaling effects of several xenoestrogens involved in early- vs. late-stage prostate cancer cell proliferation ......................................64 Abstract .............................................................................................................64 Introduction .......................................................................................................65 Materials and Methods......................................................................................68 vii Results and Discussion .....................................................................................72 Conclusions .......................................................................................................84 Chapter 4: Conclusions and Future Directions ..........................................................87 Major Conclusions from Our Studies ...............................................................87 In vivo model ....................................................................................................90 Receptor targeted agonists (Acadia ERβ agonists) ...........................................94 Other potential studies and directions ...............................................................96 References ..................................................................................................................99 Vita 154 viii List of Tables Table 2.1. Summary of mechanisms contributing to estrogen-induced decline in numbers of LAPC-4 or PC-3 prostate cancer cells. .........................60 ix List of Figures Figure 1.1. Functional domains of AR. ..................................................................19 Figure 1.2. Canonical AR signaling pathway. .......................................................21 Figure 1.3. Summary of roles for membrane and intracellular ERs. .................28 Figure 1.4. ERα and
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