CHARACTERIZING THE ROLE OF PANCREATIC STELLATE CELLS IN THE TRANSITION OF CHRONIC PANCREATITIS TO PANCREATIC CANCER
AbstractBackground- Chronic pancreatitis (CP) and pancreatic cancer are two diseases that share a mutual histological feature known as fibrosis produced by pancreatic stellate cells (PaSCs). In response to pancreatic inflammation, PaSCs are activated from quiescent phenotype into myofibroblast-like cells, which express extracellular matrix components. PaSCs are also known to facilitate the migration and invasion of pancreatic cancer cells, which are accompanied by increased matrix metalloprotease (MMP) production and epithelial-to mesenchymal transition (EMT). NADPH oxidase (Nox) is a family of enzymes that catalyze the transfer of an electron from NAD(P)H to oxygen to generate superoxide or hydrogen peroxide. Because Nox1 is expressed in PaSCs, the objective of this study was to assess the extent to which Nox1 in PaSCs facilitates the migration and invasion of pancreatic cancer cells by regulating the expression of MMP and genes involved in EMT. Results/Discussion-We found that the lack of Nox1 lowers the expression of MMP-9 mRNA and the EMT-induced gene Snail in PaSCs. Further studies need to be done in PaSCs from mice with CP and CP-associated oncogenic KRas-driven pancreatic cancer.
AffiliationDepartment of Biological Sciences
Department of Pharmacology & Toxicology
DescriptionPresentation given at the 20th Annual Phi Kappa Phi Student Research and Fine Arts Conference
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PANCREATIC STELLATE NOX 1-DERIVED ROS FACILIATE INVASION OF PANCREATIC CANCER CELLS THROUGH MATRIX METALLOPROTEINASE 9Chakraborty, Ananya; Halder, Bithika; Mondal, Souravi; Gabor Csanyi; Biological Sciences; Vascular Biology Center; Pharmacology and Toxicology; Maria Sabbatini; Augusta University (1/31/2020)Pancreatic ductal adenocarcinoma (PDAC) is a type of exocrine cancer that accounts for almost all cases of pancreatic cancer. Many studies show that chronic pancreatitis (CP), a long-term inflammation of the pancreas, is considered as the greatest risk factor for developing pancreatic cancer. We found that reactive oxygen species (ROS) generated by NADPH oxidase 1 (Nox1) in pancreatic stellate cells (PaSCs) mediate the fibrogenic process in CP. PaSCs are a class of pancreatic cells that, in the stroma surrounding pancreatic cancer cells, are known to facilitate cancer cell invasion. We found that the lack of Nox1 in PaSCs decreased the invasion of three different pancreatic cell lines using two approaches: transwell cell invasion and culture wound closure assays. The lack of Nox1 also decreased the expression of matrix metalloproteinase 9, which is an enzyme that breaks down the basal lamina, facilitating cell invasion. Using mass spectroscopy, we will assess the extent to which the lack of Nox1 in PaSCs affects the production of pro-migratory and pro-invasive proteins using mass spectroscopy. These results implicate Nox1 inhibitors as a potential therapeutic drug to impede the progression of CP to PDAC.
Nox 1-Evoked Ros Causes Fibrosis in Caerulein-Induced Chronic Pancreatitis Through the Akt PathwayChakraborty, Ananya; Department of Biological Sciences; Sabbatini, Maria; Augusta University (2019-02-13)Chronic pancreatitis (CP) manifests from a long-term inflammation, resulting in significant fibrosis of the pancreatic tissue and permanent organ damage. This occurs due to pro-inflammatory mediators, including reactive oxygen species (ROS). One of the sources of ROS is NADPH oxidase (Nox) enzymes, which transfer electrons across biological membranes to reduce oxygen to superoxide. The rodent genome encodes four Nox enzymes: Nox 1-4. We found that Nox 1 is implicated in pancreatic fibrogenesis in a mouse model of CP. Our next goal was to determine which intracellular pathway mediates the effect of Nox1-derived ROS. Several intracellular pathways are activated following Nox1-derived ROS, including JNK, AKT, and ERK1/2. Each pathway is also activated following caerulein, a cholecystokinin analogue. Our hypothesis was that repetitive administration of caerulein stimulates Nox1-derived ROS, which causes increased oxidative stress, leading to fibrogenesis through phosphorylation of ERK, AKT and JNK. We found the lack of Nox1 impaired the phosphorylation of AKT in a mouse model of CP. In conclusion, Nox1 mediates fibrogenesis through the AKT pathway in mice with CP.