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(Rage) in Progression of Pancreatic Cancer 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 8-2017 INVOLVEMENT OF THE RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS (RAGE) IN PROGRESSION OF PANCREATIC CANCER Nancy Azizian MS Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Biology Commons, and the Medicine and Health Sciences Commons Recommended Citation Azizian, Nancy MS, "INVOLVEMENT OF THE RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS (RAGE) IN PROGRESSION OF PANCREATIC CANCER" (2017). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 748. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/748 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]. INVOLVEMENT OF THE RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS (RAGE) IN PROGRESSION OF PANCREATIC CANCER by Nancy Azizian, MS APPROVED: ______________________________ Craig D. Logsdon, Ph.D. Advisory Professor ______________________________ Bill Mattox, Ph.D. ______________________________ Candelaria Gomez-Manzano, MD. ______________________________ Rebecca Berdeaux, Ph.D. ______________________________ Ralf Krahe, Ph.D. -------------------------------------------- Dean, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Science i INVOLVEMENT OF THE RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS (RAGE) IN PROGRESSION OF PANCREATIC CANCER A Dissertation Presented to the Faculty of The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY by Nancy Azizian, MS Houston, Texas August, 2017 ii INVOLVEMENT OF THE RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS (RAGE) IN PROGRESSION OF PANCREATIC CANCER Nancy Azizian, MS Advisory Professor: Craig D. Logsdon, Ph.D. Abstract. Oncogenic KRAS is central to several cancer types including pancreatic ductal adenocarcinoma (PDAC), but has been determined to be “undruggable”. Recent studies have indicated that oncogenic KRAS is not constitutively active but relies on a feed-forward stimulatory mechanism involving inflammation. In the current study we investigated the mechanisms by which, the receptor for advanced glycation end products (RAGE) affects and maintains KRAS activity. We observed that RAGE levels were elevated and there was a shift in the levels of specific isoforms upon inflammation in pancreatic cells and PDAC. Furthermore, RAGE agonists were found to increase Ras activity and downstream signaling in a time- and dose-dependent manner. Likewise, inhibition of RAGE decreased Ras signaling activity and downstream signals in multiple PDAC cell lines. In vivo, inhibition of RAGE activity using an antagonist inhibited tumor progression and increased survival rate. These data indicate that RAGE plays a central role in maintaining the activity of oncogenic KRAS and supporting tumor growth. These data raises the possibility of new approaches to inhibit the carcinogenic actions of KRAS indirectly by blocking the mechanisms through which, RAGE maintains its activity. iii Table of Contents Approval ……………………………………………………………………………………………………………………… i Title ……………………………………………………………………………………………………………………………. ii Abstract ……………………………………………………………………………………………………………………. iii Table of contents ……………………………………………………………………………………………………… iv List of illustrations ………………………………………………………………………………………………………… vii List of abbreviations ……………………………………………………………………………………………………. viii List of Tables ………………………………………………………………………………………………………………. xi Introduction …………………………………………………………………………………………………………………… 1 Chapter 1. Receptor for Advanced Glycation End Product ………………………………………… 4 1.1 RAGE Structure ………………………………………………………………………………………………………… 4 1.2 RAGE Isoforms ………………………………………………………………………………………………………….. 5 1.3 RAGE Ligands ………………………………………………………………………………………………………….. 9 1.3a. AGE ………………………………………………………………………………………………………………………. 10 1.3b. HMGB1 …………………………………………………………………………………………………………………. 12 1.3c. Amyloid Beta (Aβ) ………………………………………………………………………………………………….. 14 1.3d. S100/calgranulin Proteins ……………………………………………………………………………………. 15 1.3e. Nucleic Acids ………………………………………………………………………………………………………… 18 1.4 RAGE mediated Cell Signaling …………………………………………………………………………………… 19 1.4a. Ras ………………………………………………………………………………………………………………………… 19 1.4b. mDia1 …………………………………………………………………………………………………………………… 20 1.4c. NF-kB Pathway ………………………………………………………………………………………………………. 21 1.4d. Mitogen Activated Protein Kinases ……………………………………………………………………….. 21 1.4e. Oxidative Stress Pathways …………………………………………………………………………………… 22 1.5 RAGE expression in different Cell types ………………………………………………………………….. 22 1.5a. Endothelial Cells …………………………………………………………………………………………………… 23 iv 1.5b. SMC ……………………………………………………………………………………………………………………. 23 1.5c. CNS ……………………………………………………………………………………………………………………….. 24 1.5d. Monocytes and Macrophages……………………………………………………………………………… 24 1.5e. Granulocytes ……………………………………………………………………………………………………… 25 1.5f. Dendritic Cells (DCs) …………………………………………………………………………………………… 26 1.5g. T Cells ………………………………………………………………………………………………………………… 27 1.6 Effects of RAGE on cellular functions ……………………………………………………………………. 27 1.6a. Cell migration …………………………………………………………………………………………………….. 27 1.6b. Cell Mass and proliferation ………………………………………………………………………………… 28 1.6c. Autophagy …………………………………………………………………………………………………………. 29 1.7 RAGE and Diseases ……………………………………………………………………………………………….. 30 1.7a. Inflammation ……………………………………………………………………………………………………… 30 1.7b. RAGE and Atherosclerosis …………………………………………………………………………………… 31 1.7c. RAGE and Alzheimer’s disease …………………………………………………………………………….. 32 1.7d. Rage and Arthritis ……………………………………………………………………………………………… 32 1.7e. RAGE in cancer …………………………………………………………………………………………………… 33 1.8 RAGE inhibitors ……………………………………………………………………………………………………... 34 1.8a. FPS-ZM1 ……………………………………………………………………………………………………………. 34 1.8b. RAP (RAGE Antagonist Peptide) ………………………………………………………………………….. 35 1.8c. RAGE blocking antibodies …………………………………………………………………………………….. 35 1.8d. RAGE Aptamers ……………………………………………………………………………………………………. 36 1.8e. sRAGE ………………………………………………………………………………………………………………….. 36 Chapter 2. Materials and Methods ………………………………………………………………………………. 37 Chapter 3. Results ………………………………………………………………………………………………………… 42 3a. Pancreatic compartment expresses RAGE. ………………………………………………………………. 42 3b. Differential RAGE expression in pancreas reflects the disease state. ……………………….. 44 3c. A specific RAGE inhibitor, FPS-ZM1, blocks activation of downstream molecular signaling. ………………………………………………………………………………………………………………………. 50 3d. FPS-ZM1 downregulates methylglyoxal-induced activation of MAP kinase pathway. 53 3e. FPS-ZM1 reduces the Erk and NF-kB signaling in human pancreatic cancer cells. 54 3f. FPS-ZM1 impairs tumor progression in an in vivo mouse model. ……………………………….. 56 v Chapter 4. Discussion ………………………………………………………………………………………………. 60 Chapter 5. Concluding Remarks ……………………………………………………………………………………… 66 Chapter 6. Bibliography ……………………………………………………………………………………………...... 68 Vita ………………………………………………………………………………………………………………………….. 104 vi List of Illustrations Figure 1. Receptor for advanced glycation end-products (RAGE) structure. ………… 4 Figure 2. Primary acinar cells display increased JNK and MAPK activities in response to treatment with methylglyoxal (MG). …………………………………………………………………. 43 Figure 3. SDS-PAGE analysis of RAGE expression in pancreatic tissues. ………………….. 45 Figure 4. RAGE localization by immunohistochemistry and immunofluorescence. 47-48 Figure 5. RAGE and H2AX-Gamma foci colocalize in nucleus. ……………………………….. 49 Figure 6. RAGE inhibitor FPS-ZM1, suppresses NF-kB and Erk activities in cells expressing oncogenic KRAS, but does not suppress DNA damage signaling. ……………………………. 51 Figure 7. MAP kinase activity in KPC mouse cells is abrogated upon treatment with FPS-ZM1. ……………………………………………………………………………………………………………… 53 Figure 8. FPS-ZM1 reduces the Erk and NF-kB signaling in KPC human pancreatic cancer cells. ………………………………………………………………………………………………………………………. 55 Figure 9. Association of drug treatment with survival in orthotopic xenografts. 57 Figure 10. FPS-ZM1 treatment induces a tissue redistribution of RAGE. ……………………. 58 Figure 11. RAGE is a pattern recognition receptor involved in different cellular functions. ………………………………………………………………………………………………………………………………….. 65 vii List of Abbreviation Acronym Definition RAGE Receptor for Advanced Glycated End products PRR Pattern Recognition Receptor Ig Immunoglobulin HMGB1 High Mobility Group Box 1 MHC Major Histocompatibility Complex NF-kB Nuclear Factor kappa-light-chain-enhancer of activated B cells SP1 Specificity Protein 1 AP1 Activator Protein 1 Egr1 Early Growth Response 1 TTF1 Thyroid Transcription Factor 1 HIF1 Hypoxia-inducible Factor 1 NMD Nonsense-Mediated mRNA Degradation STZ Streptozotocin esRAGE endogenous
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