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Open RWS Final Thesis.Pdf The Pennsylvania State University The Graduate School Department of Veterinary and Biomedical Sciences THERAPEUTIC POTENTIAL OF LIGAND-ACTIVATED PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR β/δ IN PANCREATIC CANCER A Dissertation in Molecular Toxicology by Russell William Smith III 2015 Russell William Smith III Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy December 2015 The dissertation of Russell Smith was reviewed and approved* by the following: John P. Vanden Heuvel Professor of Veterinary and Biomedical Sciences Dissertation Advisor Chair of Committee K. Sandeep Prabhu Professor of Immunology and Molecular Toxicology Andrew D. Patterson Associate Professor of Molecular Toxicology Karam El-Bayoumy Distinguished Professor of Biochemistry and Molecular Biology Curtis J. Omiecinski Professor of Veterinary and Biomedical Sciences Chair of Molecular Toxicology graduate program *Signatures are on file in the graduate school iii ABSTRACT Pancreatic cancer is the fourth leading cause of cancer-related deaths with a five-year survival rate of approximately 6%. Due to its asymptomatic nature until late stages of disease, less than 10% of patients have the option for surgical resection. Smoking, alcoholism, chronic pancreatitis, and metabolic disorders such as obesity, diabetes, and atherosclerosis are associated risk factors for pancreatic cancer development. The proto-oncogene Kras is mutated in 90% of pancreatic ductal adenocarcinoma (PDAC) cases, resulting in constitutive activation. The complexity of Kras makes it a difficult therapeutic target with dysregulation affecting several downstream signaling pathways. Candidates for early prognosis detection and therapeutic targeting need to be elucidated. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors involved in terminal differentiation, glucose and lipid metabolism. Pparb is ubiquitously expressed with highest levels in the gastrointestinal tract, kidneys, and skeletal muscle. PPARβ/δ associates with the transcriptional repressor BCL6, and may be a potential target for metabolic disorders due to its ability to modulate insulin sensitivity. Furthermore, PPARβ/δ also plays a role in protecting against oxidative stress, a contributing factor towards chronic inflammation and cancer. PPARβ/δ’s role in cancer is controversial. This dissertation sought to substantiate the role of PPARβ/δ in inflammation and metastasis and to investigate its potential as a therapeutic target and prognosis marker for pancreatic cancer. In a human pancreatic cancer cell line, Mia PaCa-2, over-expression of Pparb inhibited basal and tumor necrosis factor α (TNFα)-induced nuclear factor kappa b1 (Nfkb) activity. A specific agonist of PPARβ/δ, GW501516, suppressed TNFα-induced Nfkb reporter activity. RNAi knockdown of Pparb attenuated the GW501516 effect on Nfkb luciferase activity, while knockdown of Bcl6 enhanced TNFα-induced Nfkb activity. PPARβ/δ activation induced iv expression of several anti-inflammatory genes in a dose-dependent manner, and GW501516 inhibited monocyte chemotactic protein 1 (Mcp1) promoter-driven luciferase in a BCL6- dependent manner. Pro-inflammatory genes were suppressed in a BCL6-dependent manner. GW501516-treated pancreatic cancer cell conditioned media suppressed pro-inflammatory expression in THP-1 macrophages as well as reduced invasiveness across a basement membrane. Similarly, GW501516 reduced TNFα-induced expression of several genes involved in metastasis, including Mmp9 mRNA and protein and Pparb knockdowns resulted in lower Mmp9 mRNA and protein expression. The ability of Mia PaCa-2 cells to invade an artificial basement membrane was reduced by GW501516 in a PPARβ/δ- and BCL6-dependent manner. Thus, the PPARβ/δ- BCL6 signaling pathway has an anti-inflammatory and –metastasis role in Mia PaCa-2 cells that is enhanced upon treatment with GW501516. The expression of PPARβ/δ, BCL6 and several of their target genes were examined in human PDAC, relative to matched normal pancreas tissue, and in a mouse model that mimics the human progression of disease (Pdx1-cre/LSL-KrasG12D). Pparb mRNA was over-expressed in human tumor tissue compared to normal tissue, while Bcl6 remained unaltered. Inflammatory genes that are controlled by the PPARβ/δ-BCL6 pathway were increased in the tumor tissue, including the important BCL6 target genes and pancreatic cancer prognostic indicators Mcp1 and Mmp9. Similar observations were made in the KrasG12D mice where pancreas of mice carrying this constitutively active oncogene had higher expression of Pparb mRNA, unaltered Bcl6 expression and increased Mcp1 and Mmp9 mRNA. These in vivo associations were further examined in the Mia PaCa-2 cell line. Over-expression of PPARβ/δ increased proliferation of pancreatic cancer cells, an effect that was ameliorated by GW501516. Over-expression of Pparb also increased basal and TNFα-induced Mcp1 reporter activity, which was diminished by transfection of BCL6 or treatment with GW501516. Taken together, these data strongly support a v sequestering of BCL6 by PPARβ/δ that occurs during the progression of PDAC when dysregulation results in over-expression of PPARβ/δ. The data presented herein supports a dichotomous role for the PPARβ/δ-BCL6 in the pancreatic cancer. Over-expression of PPARβ/δ, through sequestering of the transcription repressor BCL6, enhances the expression of genes known to be involved in PDAC progression such as Mcp1 and Mmp9. However, upon treatment with the PPARβ/δ ligand GW501516, these same genes are repressed by the dual action of PPARβ/δ and BCL6. Taken together, this has important implications for pancreatic cancer therapy as well as diagnosis. Treatment with a specific PPARβ/δ ligand, such as GW501516, decreases inflammatory signaling and reduces macrophage recruitment, thereby limiting tumor progression. Also, via release of BCL6, the expression of metastatic proteins such as Vcam1 and Mmp9 is reduced, thereby decreasing metastatic potential. From a prognostic standpoint, it would be expected that a patient with higher expression of PPARβ/δ, and hence a repression of BCL6 signaling, in tumor tissue would benefit more significantly from GW501516 treatment. Combined with drugs that inhibit pancreatic cancer cell proliferation, GW501516 has the potential to be an effective tool in the fight against pancreatic cancer. vi TABLE OF CONTENTS List of Figures .......................................................................................................................... viii List of Tables ........................................................................................................................... ix List of Abbreviations ............................................................................................................... x Acknowledgements .................................................................................................................. xii Chapter 1 Literature review ..................................................................................................... 1 1.1 Pancreatic cancer ........................................................................................................ 1 1.1.1 Chemotherapy ................................................................................................. 3 1.1.2 Etiology ........................................................................................................... 4 1.1.3 Epidemiology .................................................................................................. 6 1.1.4 Molecular biology ........................................................................................... 7 1.1.5 Inflammation ................................................................................................... 9 1.1.6 Physiology ....................................................................................................... 11 1.1.7 Stages .............................................................................................................. 12 1.1.8 Cell lines .......................................................................................................... 14 1.2 Mouse models of pancreatic cancer ........................................................................... 16 1.2.1 Pdx1 Cre mouse .............................................................................................. 18 1.2.2 LSL KrasG12D mouse ....................................................................................... 18 1.2.3 Cre-activated KrasG12D .................................................................................... 18 1.3 Peroxisome proliferator-activated receptors .............................................................. 19 1.3.1 PPARβ/δ .......................................................................................................... 23 1.3.2 DNA binding ................................................................................................... 24 1.3.3 Association with BCL6 ................................................................................... 25 1.3.4 Gene regulation ............................................................................................... 26 1.4 Roles of PPARβ/δ ...................................................................................................... 28 1.4.1 Oxidative stress ............................................................................................... 28 1.4.2 Metabolic
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