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The Effect of Indole-3-Carbinol and 3,3’-Diindolylmethane on Fatty Acid Synthase and Sp1 in Breast Cancer Cells

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The Effect of Indole-3-Carbinol and 3,3’-Diindolylmethane on Fatty Acid Synthase and Sp1 in Breast Cancer Cells THE EFFECT OF INDOLE-3-CARBINOL AND 3,3’-DIINDOLYLMETHANE ON FATTY ACID SYNTHASE AND SP1 IN BREAST CANCER CELLS by George Eramiah Saati A thesis submitted in conformity with the requirements for the degree of Master of Science Graduate Department of Nutritional Sciences University of Toronto © Copyright by George Eramiah Saati 2009 THE EFFECT OF INDOLE-3-CARBINOL AND 3,3’-DIINDOLYLMETHANE ON FATTY ACID SYNTHASE AND SP1 IN BREAST CANCER CELLS Master of Science, 2009 George Eramiah Saati Graduate Department of Nutritional Sciences University of Toronto ABSTRACT Fatty acid synthase (FAS), an enzyme that is over-expressed in many cancers, is necessary for cancer cell proliferation. Previously, we have shown that FAS in cancer cells is regulated at least in part, by Sp1. Indole-3-carbinol (I3C) and its acid condensation product, 3,3’- diindolylmethane (DIM) modulate various transcription factors involved in regulating cellular proliferation and apoptosis. The objective of this study was to determine whether reductions in breast cancer cell proliferation caused by I3C and/or DIM occur as a result of reductions in FAS. DIM and, in some cases, I3C reduced FAS expression in three breast cancer cell lines. However, addition of palmitate or oleate to DIM-treated MCF-7 cells did not restore proliferation. DIM- associated reduction in proliferation of MCF-7 cells also results in a reduction of Sp1 expression, and down-regulation of FAS occurs after inhibition of proliferation. Thus, the anti-proliferative effect of I3C and DIM may be due to their effect on down-regulating Sp1, which in turn could modify several Sp1-associated genes, including FAS. ii ACKNOWLEDGEMENTS There are a number of special people who were instrumental in making my graduate experience, one of great enlightenment, excitement and accomplishment. I would like to extend my sincere gratitude to them here. First, I would like to thank my supervisor Dr. Michael Archer. Over the past two years, Dr Archer has shared with me a wealth of knowledge, and given me the encouragement I’ve needed to successfully complete this degree. He is a true gentleman and everyday around him has truly felt like a privilege. The ways he approaches situations in science and life are some of the most rewarding experiences I’ve ever received. Dr. Archer has helped me mature as an academic and a person. I will take what I have learned from him and do my best to apply as much of it as I can to my life, in hopes that someday I too can lead myself, my family or an organization to success – like him. I would also like to thank my committee members, Dr. Ahmed El-Sohemy and Dr. Richard Bazinet. I feel very privileged to have met these gentlemen and believe they both will change the way our world understands nutrition. Dr. El-Sohemy, as one of my committee members, I am sincerely grateful for your help and advice in completing my thesis work and experiments. I also would like to thank you for introducing me to the world of nutritional sciences and research, and for granting me the reference letters and referrals that made it into the hands of Dr. Archer. Without your help, I don’t know if I would have made it this far academically. Dr. Bazinet, I am extremely honoured to have had the opportunity to have had you on my committee. Your unparalleled wisdom, expertise and support were paramount in the progress and completion of this project. I thank you whole-heartedly for your all your help and suggestions. iii I will always be grateful to the people of Archer lab, whose help has been invaluable in all the years that I have worked in their lab. I would like to thank Suying Lu, Kafi Ealey, Guodong Liu, Dominic Lau and Wanli Xuan for all their helpful advice and technical assistance. I am grateful for their friendship and for making my laboratory experience an enjoyable one. I also want to thank my external examiner, Dr. Wendy Ward, and my examination chair, Dr. Hanley for being very accommodating and for offering helpful feedback and comments. Next, I’d like to thank the many graduate students and friends who have made my stay here memorable. To Jennifer Truan, Amin Esfahani, Pedro Huot, Sandra Sacco, Alireza Jahanmihan, Dennis Wagner, Jovanna Kaludjerovic, Sandra Reza-Lopez, Josh Green, Amanda Carleton and Julie Mason, I will always be grateful for meeting you. The coffee breaks, the pubs, the restaurants downtown and, of course, the troubleshooting of experiments – I’m very thankful for being able to have shared these experiences with you. Lastly, I would like to express my utmost love and gratitude to my family. My mother and father have given me an enormous amount of help and understanding and have provided me with food and shelter every single day. Also, my brother and my sister have always been there to lighten my day when I get home. Thank you all for putting up with me during my ups and downs. My family’s continued love and support over the years have helped me become who I am today, and for that, I will be forever grateful. iv TABLE OF CONTENTS CHAPTER ONE: INTRODUCTION AND LITERATURE REVIEW…………………...….1 Introduction To Diet and Cancer………………………………………………………………….2 Introduction To Thesis…………………………………………………………………………….4 1.1 Cruciferous Vegetables………………………………………………………………………..4 1.1.1 Glucosinolates……………………………………………………………………………….5 1.1.2 Activation of Glucosinolates by Myrosinase………………………………………………..8 1.1.3 Factors Influencing Myrosinase Activity…………………………………………………....9 1.1.4 Bioactive Glucosinolate Products………………………………………………………….11 1.2 Indole-3-Carbinol (I3C) and 3,3'-Diindolylmethane (DIM)…………………………………11 1.2.1 Tissue Distribution, Intake Levels and Physiologic Concentrations………………………12 1.2.2 Cancer Protective Effects of I3C and DIM in Rodents ……………………………………13 1.2.3 Cancer Protective Effects of I3C and DIM in Humans……………………………………17 1.2.4 Anticancer Effects of I3C and DIM in vitro: Possible Mechanisms of Action ……………17 1.3 Fatty Acid Synthesis…………………………………………………………………………22 1.3.1 Fatty Acid Synthase (FAS) and de novo Generation of Palmitate…………………………23 1.3.2 FAS in Normal Tissues…………………………………………………………………….26 1.3.3 Inhibitors of FAS…………………………………………………………………………..27 1.3.4 Regulation of FAS…………………………………………………………………………30 1.3.4.1 Short-term Regulation of FAS…………………………………………………………...30 1.3.4.2 Long-term Regulation of FAS…………………………………………………………...31 1.3.5 Transcription of FAS………………………………………………………………………32 1.4 FAS and Cancer……………………………………………………………………………...35 1.4.1 FAS and Breast Cancer ……………………………………………………………………36 1.4.2 FAS and Other Cancers……………………………………………………………………38 1.4.3 Regulation of FAS in Cancer………………………………………………………………38 1.4.4 Transcription Factors Regulating FAS…………………………………………………….40 1.4.5 Specificity Protein 1 (Sp1) in Cancer…………...…………………………………………42 1.5 Research Hypothesis and Objectives………………………………………………………...44 v CHAPTER TWO: MATERIALS AND METHODS…………………………………………46 2.1 Cell Culture Conditions……………………………………………………………………...47 2.2 Cell Treatment……………………………………………………………………………….47 2.3 Cell Viability Analysis……………………………………………………………………….48 2.4 Preparation of Whole Cell Extracts and Western Blot Analysis……………………………..48 2.5 Preparation of Total RNA……………………………………………………………………49 2.6 Preparation of cDNA and Real-time PCR Analysis………………………………………….50 2.7 Rescue Experiments………………………………………………………………………….51 2.8 Inhibition of FAS with Cerulenin……………………………………………………………52 2.8 Statistical Analysis…………………………………………………………………………...52 CHAPTER THREE: RESULTS……………………………………………………………….53 3.1 The Effect of I3C on MCF-7 Cells…………………………………………………………..54 3.2 The Effect of DIM on MCF-7 Cells………………………………………………………….56 3.3 The Effect of I3C and DIM on MDA-MB-231 Cells………………………………………..59 3.4 The Effect of I3C and DIM on SKBR-3 Cells……………………………………………….61 3.5 MCF-7 Proliferation Restoration Experiments………………………………………………61 3.6 The Effect of DIM on MCF-10A Cells………………………………………………………64 3.7 The Effect of Cerulenin on MCF-10A Proliferation…………………………………………66 CHAPTER FOUR: GENERAL DISCUSSION AND CONCLUSION……………………...68 4.1 Discussion……………………………………………………………………………………69 4.2 Conclusion…………………………………………………………………………………...77 4.3 Implications………………..………………………………………………………………...77 4.4 Limitations and Future Directions..………………………………………………………….78 REFERENCES…………………………………………………………………………………81 vi LIST OF TABLES Table 1.1 - Food sources of selected glucosinolates and their hydrolysis products that are currently under investigation for their cancer chemopreventative properties…………………….7 Table 4.1 – The effect of I3C on proliferation, FAS and Sp1 expression in MCF-7, MDA-MB- 231 and SKBr-3 cells……………………………………………………………….……………70 Table 4.2 – The effect of DIM on proliferation, FAS and Sp1 expression in MCF-7, MDA-MB- 231, SKBr-3 and MCF-10A cells………………………………………….…………………….70 vii LIST OF FIGURES Figure 1.1 - General chemical structure of a glucosinolate molecule…………………………….5 Figure 1.2 - Bioactivation of glucosinolates……………………………………………………...9 Figure 1.3 - Molecular structures of I3C and DIM……………...…………………………...….12 Figure 1.4 – Glycolysis and fatty acid synthesis………………………………………………...23 Figure 1.5 - Palmitate synthesis in FAS enzyme complex……………………………………...25 Figure 1.6 - The FAS promoter region and transcription factor binding areas………………….32 Figure 1.7 - Regulation of FAS expression in cancer by growth factors and steroid hormones…….……………………………………………………………………...39 Figure 1.8 - Post-translational regulation of FAS in cancer by USP2a…………………………40 Figure 3.1 - The effect of I3C on MCF-7 proliferation after 48 h and 72 h…………………….55 Figure 3.2 - The effect of I3C on FAS expression in
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