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The Protective Effects of Conjugated Linoleic Acid Against Carcinogenesis

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The Protective Effects of Conjugated Linoleic Acid Against Carcinogenesis The Protective Effects of Conjugated Linoleic Acid Against Carcinogenesis Item Type text; Electronic Dissertation Authors Kemp, Michael Quentin Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 24/09/2021 15:13:15 Link to Item http://hdl.handle.net/10150/193637 THE PROTECTIVE EFFECTS OF CONJUGATED LINOLEIC ACID AGAINST CARCINOGENESIS by Michael Quentin Kemp A Dissertation Submitted to the Faculty of the GRADUATE PROGRAM IN NUTRITIONAL SCIENCES In Partial Fulfillment of the Requirements for the Degree of DOC TORAL OF PHILOSOPHY In the Graduate College THE UNIVERSITY OF ARIZONA 2005 2 THE UNIVERSITY OF ARIZONA GRADUATE COLLEGE As members of the Dissertation Committee, we certify that we have read the dissertation prepared by Michael Q. Kemp entitled The Protective Effec ts of Conjugated Linoleic Acid Against Carcinogenesis and recommend that it be accepted as fulfilling the dissertation requirement for the Deg ree of Doctor of Philosophy _______ ___________________________ __________________ ________ _______ ___ _ Date : 11/18/05 . Donato Romagnolo _______ ___________________________ __________________ ________ ___________ Date: 11/18/05 . Wanda Howell _______ ___________________________ __________________ ________ ___________ Date: 11/18/05 . Linda Houtkooper _______ ___________________________ __________________ ________ ___________ Date: 11/18/05 . Scott Going _______ ___________________________ __________________ ________ ___________ Date: 11/18/05 . Joy Winzerling Final approval and acceptance of this dissertation is contingent upon the candidate’s submission of the final copies of the dissertation to the Graduate College. I hereby certify that I have read this dissertation prepar ed under my direction and recommend that it be accepted as fulfilling the dissertation requirement. ________________________________________________ Date : 11/18/05 . Dissertation Director: Donato Romagnolo 3 STATEMENT BY AUTHOR This diss ertation has been submitted in partial fulfillment of requirements for an advanced degree at The University of Arizona and is deposited in the University Library to be made available to borrowers under rules of the Library. Brief quotations from this diss ertation are allowable without special permission, provided that accurate acknowledgment of source is made. Requests for permission for extended quotation from a reproduction of this manuscript in whole or in part may be granted by the head of the major department of the Dean of the Graduate College when in his or her judgment the proposed use of the material is in the interests of scholarship. In all other instances, however, permission must be obtained from the author. SIGNED: Michael Q Kemp . 4 ACKNOWLEDGMENTS I would first like to thank my mentor and graduate advisor, Dr. Donato Romagnolo, for providing me the opportunity to work in his laboratory. His guidance has proven invaluable in helping me think critically to become a better scientist. I would also like to thank my committee members, Dr. Wanda Howell, Dr. Linda Houtk ooper, Dr. Scott Going, and Dr. Joy Winzerling for their beneficial comments and advice. I would also like to thank the past and present members of the R omagnolo laboratory. 5 TABLE OF CONTENTS LIST OF FIGURES…………………………………………………………………….8 LIST OF TABLES.........................................................................................................10 ABSTRACT …………………………………………………………………………..11 CENTRAL HYPOTHESIS ..……………………………………………………….....12 RELEVANCE …………………………………………………………………….......13 SPECIFIC AIMS ..................………………………………………………………….14 CHAPTER 1: INTRODUCTION ……...…………………………….……………….15 Conjugated Linoleic Acid ……………………………………………………...17 Conjugated Linoleic Acid as Breast Anticarcinogen ………………………..…22 Cell Cycle ……………………………………………………………………...24 Polycyclic Aromatic Hydrocarbons as Risk Factors in Breast Carcinogenesis ..27 Susceptibility of DNA Damage from PAHS: AhR Pathway. .......................... ..29 Cyclooxygenase and Breast Cancer ...................................................................30 PAHs as Substrates and Inducers of COX -2......................................................33 CLA Attenuates COX -2 Expression..................................................................37 CHAPTER 2: MATERIALS AND METHODS ...........................................................38 Cell Culture ........................................................................................................38 Trypan Blue Exclusion.......................................................................................38 Methylthiazolydiphenyl -tetrazolium Bromide...................................................39 Flow Cytometry .................................................................................................39 Western Blotting................................................................................................39 6 TABLE OF CONTENTS -CONTINUED Transient Transfections ......................................................................................40 Mutagenesis ........................................................................................................41 DNA -Protein Binding..........................................................................................41 Data Collection and Statistical Analysis .............................................................43 CHAPTER 3: CONJUGATED LINOLEIC ACID INHIBITS CELL PROLIFERATION THROUGH A P53-DEPENDENT MECHANISM: EFFECTS ON THE EXPRESSION OF THE G1 -RESTRICTION POINTS IN BREAST AND COLON CANCER...........44 Abstract ...............................................................................................................45 Introduction.........................................................................................................46 Results .................................................................................................................49 Discussion...........................................................................................................63 CHAPTER 4: CONJUGATED LINOLEIC ACID INHIBITS POLYCYCLIC AROMATIC HYDROCARBON -INDUCED CYCLOOXYGENASE -2 PROMOTER ACTIVITY THROUGH AND AROMATIC HYDROCARBON RECEPTOR - DEPENDENT MECHANISM........................................................................................68 Abstract ...............................................................................................................69 Introduction.........................................................................................................70 Results .................................................................................................................73 Dis cussion...........................................................................................................89 CHAPTER 5: SUMMARY AND CONCLUSIONS ......................................................95 Conclusions.........................................................................................................95 7 TABLE OF CONTENTS -CONTINUED Future Directions..................................................................................................99 APPENDIX A. ABBREVIATIONS ..…………………....…………………...….……100 APPENDIX B. PERMISSION TO REPRINT COPYRIG HTED MATERIALS..…….102 APPENDIX C. PUBLISHED MATERIALS ..................................................................103 REFERENCES ................................................................................................................104 8 LIST OF FIGURES Figure 1. Proposed Model ..................................................................................................16 Figure 2. Structures of cis9trans11-CLA, tr ans10cis12-CLA and linoleic acid...............18 Figure 3. Metabolic interme diates of linoleic and linolenic acid produced by rumen bacteria ..............................................................................................................................21 Figure 4. Cell cycle and its arrest ......................................................................................26 Figure 5. Structure of the PAH, Benzo[a]pyrene ..............................................................28 Figure 6. Cyclooxygenase synthesis of prostaglandins via arachidonic acid ....................32 Figure 7. Activation of B[a]P by COX enzymes ..............................................................34 Figure 8. Identification of cis -acting elements in human COX -2 promoter ......................36 Fi gure 9. Treatment with a CLA mix ture reduces the growth rate of breast cancer MCF -7 cells ....................................................................................................................................50 Figure 10. Treatment with CLA mixture induces G1 arrest and modulate s the expression of G1 checkpoints .............................................................................................................53 Figure 11. CLA delays exit of MCF -7 cells from G0/G1 arrest. ......................................56 Figure 12. Wild -type p53 is required for CLA -dependent down -regulation of cyclinE in breast cancer MCF -7 cells. ...............................................................................................57
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