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Anticancer Mechanisms of Flaxseed and Its Derived Mammalian

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Anticancer Mechanisms of Flaxseed and Its Derived Mammalian ANTICANCER MECHANISMS OF FLAXSEED AND ITS DERIVED MAMMALIAN LIGNAN ENTEROLACTONE IN LUNG A Dissertation Submitted to the Graduate Faculty of the North Dakota State University of Agriculture and Applied Science By Shireen Chikara In Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY Major Program: Cellular and Molecular Biology April 2017 Fargo, North Dakota North Dakota State University Graduate School Title ANTICANCER MECHANISMS OF FLAXSEED AND ITS DERIVED MAMMALIAN LIGNAN ENTEROLACTONE IN LUNG By Shireen Chikara The Supervisory Committee certifies that this disquisition complies with North Dakota State University’s regulations and meets the accepted standards for the degree of DOCTOR OF PHILOSOPHY SUPERVISORY COMMITTEE: Dr. Katie Reindl Chair Dr. Jane Schuh Dr. Yeong Rhee Dr. Steven Qian Approved: 04-13-2017 Dr. Jane Schuh Date Department Chair ABSTRACT Whole flaxseed and its derived lignans have shown anti-cancer properties in a variety of malignancies. However, their potential remains uninvestigated in lung cancer, the leading cause of cancer-related deaths worldwide. We investigated the anti-tumor effects of flaxseed-derived mammalian lignan enterolactone (EL) in human lung cancer cell cultures and the chemopreventive potential of 10% whole flaxseed in a mouse model of lung carcinogenesis. We found that EL inhibits in vitro proliferation and motility of a panel of non-small cell lung cancer cell (NSCLC) lines. EL-mediated inhibition in lung cancer cell proliferation was due to a decrease in mRNA and protein expression levels of G1-phase cell cycle promoters and a simultaneous increase in mRNA and protein expression levels of p21WAF1/CIP1, a negative regulator of the G1-phase. Similarly, EL decreased lung cancer cell motility by modulating cytoskeleton organization, inhibiting the activation of the FAK-Src-paxillin signaling cascade, and expression of down-stream motility regulators. Our in vivo investigation revealed that 10% whole flaxseed reduced the incidence, number, and size of lung tumor nodules in A/J mice exposed to the tobacco smoke carcinogen, nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK). RNA sequencing revealed altered expression of genes whose products modulate inflammation and oxidative stress, and are likely to be responsible for chemopreventive potential of whole flaxseed. The results from our in vitro studies highlight the anticancer potential of EL in lung cancer, while the results from our in vivo study show that whole flaxseed holds promise as a chemopreventive dietary agent in lung. iii ACKNOWLEDGEMENTS I started my PhD in Cellular and Molecular Biology program in the Biological Sciences Department at NDSU in Fall 2010 and have been fortunate to be surrounded by people who always had confidence in me. At the outset, I take this opportunity to thank Dr. Katie Reindl, my advisor, whose unwavering support and guidance helped me complete my research and made this thesis possible. The time and energy that she devoted to me, and the patience she has shown in helping me improve on my weaker areas have honed my research and scientific writing skills. Dr. Reindl, thank you so much for all your help and guidance over the past six years. I am grateful to Drs. Jane Schuh, Yeong Rhee, and Steven Qian, members of my thesis committee, for their valuable suggestions and advice over the course of my research. I would also like to thank Dr. Pawel Borowicz for his insightful suggestions and guidance on various experiments and Jordon Flaten for assistance with the same. I would like to acknowledge Jeffery Kittilson for his support in trouble shooting with experiments. He is the go-to person for every graduate student in the department. This section would be incomplete without fond appreciation of all graduate and undergraduate students in my lab who have been a part of my joyous graduate school ride. I would specifically like to mention Kaitlin Lindsey for being a dedicated undergraduate student and for assisting me in my experiments and my dear friend, Dr. Harsharan Dhillon, with whom I spent most of my time during my doctoral studies. I have been fortunate to have a loving and supportive family, my father (Dr. Devendra Chikara), mother (Dr. Anita Chikara), and brother (Abhishek Chikara), who are my pillars of strength. My father’s warm love and endless care for me is beyond description. This work would iv not have seen the light of the day if he had not supported and encouraged me throughout my journey as a PhD student. v DEDICATION This thesis is dedicated to my father, Dr. Devendra Chikara. His untiring support, and encouragement have made this dissertation possible. He has been the wind beneath my wings. Thank you for everything! vi TABLE OF CONTENTS ABSTRACT ................................................................................................................................... iii ACKNOWLEDGEMENTS ........................................................................................................... iv DEDICATION ............................................................................................................................... vi LIST OF TABLES ....................................................................................................................... xiii LIST OF FIGURES ..................................................................................................................... xiv LIST OF ABBREVIATIONS ....................................................................................................... xv CHAPTER 1. GENERAL INTRODUcTION, OBJECTIVES AND SPECIFIC AIMS ................ 1 Introduction ................................................................................................................................. 1 Lung cancer statistics .................................................................................................................. 3 Lung cancer types ........................................................................................................................ 3 History of tobacco smoking and risk of lung cancer ................................................................... 4 Tobacco-smoke constituents and their potential carcinogenicity in lung ................................... 5 Etiology of lung cancer ............................................................................................................... 7 NNK-induced DNA adducts: mutations in critical genes ........................................................... 9 TP53 ...................................................................................................................................... 10 KRAS .................................................................................................................................... 10 Cell cycle regulation .................................................................................................................. 11 Cell cycle deregulation in lung carcinogenesis ..................................................................... 12 Treatment modalities for NSCLC ............................................................................................. 13 Surgery .................................................................................................................................. 13 Traditional chemotherapy ...................................................................................................... 13 Targeted therapy .................................................................................................................... 14 Anti-EGFR therapies ......................................................................................................... 14 Anti-KRAS therapies ......................................................................................................... 15 vii Limitations of current NSCLC treatment modalities ................................................................ 16 Anticancer role of whole foods and their derived bioactive components in lung ..................... 17 Flaxseed and its phytochemicals ............................................................................................... 19 Flaxseed and its derived lignans in treatment of cancer ............................................................ 21 Breast cancer ......................................................................................................................... 21 Colon cancer .......................................................................................................................... 22 Prostate cancer ....................................................................................................................... 22 Flaxseed and its chemopreventive potential .............................................................................. 23 Breast cancer ......................................................................................................................... 23 Colon cancer .......................................................................................................................... 24 Prostate cancer ....................................................................................................................... 25 Lung cancer chemoprevention .................................................................................................. 25 Rationale for the use of enterolactone in lung cancer treatment and flaxseed in chemoprevention
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