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CHARACTERIZING THE ROLE OF PANCREATIC STELLATE CELLS IN THE TRANSITION OF CHRONIC PANCREATITIS TO PANCREATIC CANCERGodoy, Catalina; Department of Biological Sciences; Department of Pharmacology & Toxicology; Csanyi, Gabor; Sabbatini, Maria; Augusta University (2019-02-13)Background- 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.
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.
STRUCTURAL AND FUNCTIONAL PROPERTIES OF ADENYLYL CYCLASE-ASSOCIATED PROTEIN 1/ADENYLYL CYCLASE COMPLEXES IN PANCREATIC CANCER CELLSMehrotra, Simran; Department of Biological Sciences; Sabbatini, Maria; Augusta University (2019-02-13)Of all the different cancers, pancreatic cancer is one of the major unsolved health problems. It is important to study the mechanism through which the pancreatic cells migrate to prolong survival in patients. Concerning the progression of pancreatic cancer, the adenylyl cyclase (AC)/adenosine 3�,5� cyclic monophosphate (cyclic AMP) pathway has shown to inhibit in the migration of pancreatic cancer cells. �Adenylyl cyclase- associated protein 1 (CAP1) is a protein that is involved in the regulation of actin microfilament formation, which ultimately leads to cell migration and invasion. The CAP 1 protein binds to G-actin, inhibiting polymerization which inhibits filopodia formation, inhibiting cell migration. In a previous research project in the lab it was found that CAP 1 reacts with different adenylyl cyclase (AC) isoforms: AC1, AC3, AC4 and AC7. behavior. The objective of this research was, through theoretical and experimental analyses, to determine to which extent CAP1 interacts with the 4 transmembrane AC isoforms mentioned above.�Through a sequential co-immunoprecipitation approach, I determined which AC isoform experimentally has a higher affinity for CAP1 using the HPAC cell line, which is moderately differentiated. Based on the theoretical and experimental results, AC3 and AC4 have the highest affinity for CAP1.