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THE ROLE of TAK1 in PANCREATIC CANCER DEVELOPMENT Qianghua Xia

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THE ROLE of TAK1 in PANCREATIC CANCER DEVELOPMENT Qianghua Xia The Texas Medical Center Library DigitalCommons@TMC The University of Texas MD Anderson Cancer Center UTHealth Graduate School of The University of Texas MD Anderson Cancer Biomedical Sciences Dissertations and Theses Center UTHealth Graduate School of (Open Access) Biomedical Sciences 12-2011 THE ROLE OF TAK1 IN PANCREATIC CANCER DEVELOPMENT qianghua xia Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Cancer Biology Commons Recommended Citation xia, qianghua, "THE ROLE OF TAK1 IN PANCREATIC CANCER DEVELOPMENT" (2011). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 201. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/201 This Dissertation (PhD) is brought to you for free and open access by the The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at DigitalCommons@TMC. It has been accepted for inclusion in The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access) by an authorized administrator of DigitalCommons@TMC. For more information, please contact [email protected]. THE ROLE OF TAK1 IN PANCREATIC CANCER DEVELOPMENT AND THE MECHANISM OF TAK1 REGULATION By Qianghua Xia, M.S. APPROVED: _________________________________ Paul Chiao, Ph.D., Supervisory Professor _________________________________ Peng Huang, M.D., Ph.D. _________________________________ Wei Zhang, Ph.D. _________________________________ Shao-Cong Sun, Ph.D. _________________________________ Bingliang Fang, M.D., Ph.D. APPROVED: ____________________________ Dean, The University of Texas Graduate School of Biomedical Sciences at Houston THE ROLE OF TAK1 IN PANCREATIC CANCER DEVELOPMENT AND THE MECHANISM OF TAK1 REGULATION A DISSERTATION Presented to the Faculty of The University of Texas Health Science Center at Houston and The University of Texas M. D. Anderson Cancer Center Graduate School of Biomedical Sciences in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY -------------------------------------------- By Qianghua Xia, M.S. Houston, Texas August 2011 ACKNOWLEDGEMENTS I would like to express my deepest gratitude to Dr. Paul Chiao for his support throughout my scientific endeavor, without which this project would never have reached fruition. I will always remember his charming personality, patience and kindness. I would like to thank Dr. Peng Huang, Dr. Shao-Cong Sun, Dr. Bingliang Fang, Dr. Kwong-Kwok Wong, Dr. Wei Zhang and Dr. Reuben Lotan for serving on my Ph.D. committee. I would like to say special thanks to Dr. Yi Shi for his help with the MASS SPEC analysis, to Dr. Ruiying Zhao for her help with establishing cell lines. In addition, I want to express my appreciation to my colleagues in the laboratory: Dr. Zhongkui li, Dr. Jianghua Lin, Dr. Zhe Chang, Dr. Yaan Kang, Ms. Yu Cao. It was a pleasure working with all of you. Above all, I would like to thank my family for their endless support throughout my life. iii THE ROLE OF TAK1 IN PANCREATIC CANCER DEVELOPMENT AND THE MECHANISM OF TAK1 REGULATION Publication Number: _________ Qianghua Xia, M.S. Supervisory Professor: Paul Chiao, Ph.D. Pancreatic cancer is the fourth leading cause of cancer-related mortality in the United States and the fifth leading cause of cancer-related mortality worldwide. Pancreatic cancer is a big challenge in large due to the lack of early symptoms. In addition, drug resistance is a major obstacle to the success of chemotherapy in pancreatic cancer. The underlying mechanism of drug resistance in human pancreatic cancers is not well understood. Better understanding of the mechanism of molecular pathways in human pancreatic cancers can help to identify the novel therapeutic target candidates, and develop the new preventive and clinic strategies to improve patient survival. We discovered that TAK1 is overexpressed in pancreatic cancer cell lines and patient tumor tissues. We demonstrated that the elevated activity of TAK1 is caused by its binding partner TAB1. Knocking down of TAK1 in pancreatic cancer cells with RNAi technique resulted in cell apoptosis and significantly reduces the size of tumors in mice and made a chemotherapy drug more potent. Targeting the kinase activity of TAK1 with the selective inhibitor LY2610956 strongly synergized in vitro with the antitumor activity of gemcitabine, oxaliplatin, or irinotecan iv on pancreatic cancer cells. These findings highlighted that TAK1 could be a potential therapeutic target for pancreatic cancer. We also demonstrated that TAK activity is regulated by its binding protein TAB1. We defined a minimum TAB1 sequence which is required and sufficient for TAK1 kinase activity. We created a recombinant TAK1-TAB1 C68 fusion form which has highly kinase activity. This active form could is used for screening TAK1 inhibitors. In addition, several posttranslational modifications were identified in our study. The acetylation of lysine 158 on TAK1 is required for kinase activity. This site is conserved throughout all of kinase. Our findings may reveal a new mechanism by which kinase activity is regulated. v TABLE OF CONTENTS Approval Page ..........................................................................................................................i Title Page ................................................................................................................................ ii Acknowledgements ................................................................................................................ iii Abstract ...................................................................................................................................iv Table of Contents .................................................................................................................. vii List of Illustrations ............................................................................................................... vi List of Tables ..................................................................................................................... vi List of Abbreviations .................................................................................................... xviii CHAPTER 1. THE ROLE OF TAK1 IN PANCREATIC CANCER TUMORIGENESIS 1.1. Introduction.........................................................................................................................1 1.1.1. Overview of pancreas......................................................................................................1 1.1.1.1. Function and anatomy of Pancreas ........................................................................1 1.1.1.2. The origin of pancreatic cell lineage.......................................................................2 1.1.2. Overview of pancreatic cancer.........................................................................................5 1.1.2.1. Causes and risk factors of pancreatic cancer .........................................................5 1.1.2.2. The classification of ductal adenocarcinoma of the pancreas................................5 1.1.2.2.1. Pancreatic intraepithelial neoplasia (PanIN) .....................................................6 1.1.2.2.1.1. PanIN-1A.........................................................................................................7 1.1.2.2.1.2. PanIN-1B.......................................................................................................7 1.1.2.2.1.3. PanIN-2.........................................................................................................7 vi 1.1.2.2.1.4. PanIN-3.........................................................................................................9 1.1.2.2.1.5. Genetic alterations in pancreatic adenocarcinoma............................................9 1.1.2.2.1.5.1. K-RAS ........................................................................................................10 1.1.2.2.1.5.2. P21WAF1/CIP1 .................................................................................................11 1.1.2.2.1.5.3. HER-2/neu .................................................................................................11 1.1.2.2.1.5.4. Loss of p16 protein ....................................................................................11 1.1.2.2.1.5.5. The p53 tumor suppressor ...........................................................................12 1.1.2.2.1.5.6. Loss of SMAD4 ..........................................................................................12 1.1.2.2.1.5.7. BRCA2 mutation ........................................................................................12 1.1.2.2.1.6. Other signaling pathways in PDAC................................................................13 1.1.2.2.1.6.1. Growth factor pathways in pancreatic cancer..............................................13 1.1.2.2.1.6.2. The serine/threonine kinase LKB1..............................................................12 1.1.2.2.1.6.3. NF-κB transcriptional factor in pancreatic cancer ......................................14 1.1.2.2.2. Mucinous cystic neoplasms (MCNs) ................................................................15 1.1.2.2.3. Intraductal papillary mucinous neoplasms (IPMNs) ........................................16 1.1.2.3. Mouse models
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