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Effectors Implicated In the Ac1 Inhibitory Effect on Cell Proliferation in Pancreatic Cancer CellsIntroduction and aim: Pancreatic adenocarcinoma is among the most aggressive of all cancers. Adenosine 3’, 5’ cyclic monophosphate (cyclic AMP) is involved in the internal cellular enzymatic activity and gene expression. It is found to be involved in the mechanism of pancreatic tumorigenesis. So far, two effectors for cyclic AMP are known; one is protein kinase A (PKA) and the other is an exchange protein directly activated by cAMP (EPAC). Our research group has found that AC1 is responsible for the inhibitory effect of Forskolin on cell proliferation of HPAC. My research project focuses on studying the effectors implicated in the inhibitory effect of activated AC1. Result: We were successfully able to overexpress AC1 using a plasmid human ADCY1 cDNA in pCMV-SPORT6. Through the overexpression, we were able to support the conclusion that AC1 inhibits cell proliferation in HPAC cells. We found that both H-89 (inhibitor of PKA) and ESI (inhibitor of EPAC) counteracts the effect of AC1. Conclusion: Both effectors- PKA and EPAC- mediate the inhibitory effect of AC1. Funding Source: Center for Undergraduate Research and Scholarship and Department of Biological Sciences, Scholarly Activity Award
Effectors Implicated in the Adenylyl Cyclase 1 Inhibitory Effect on Cell Migration in Pancreatic Cancer CellsPancreatic adenocarcinoma is among the most aggressive of all cancers in the United States. Cyclic adenosine monophosphate (cyclic AMP) is a second messenger that regulates the proliferation and migration of pancreatic cancer cells. Cyclic AMP is formed from cytosolic ATP by the enzyme adenylyl cyclase (AC). In the presence of forskolin, a transmembrane AC activator, the proliferation and migration of pancreatic cells have been inhibited. Since the mechanisms underlying the inhibitory effect of activated adenylyl cyclase are little understood, we investigated the downstream mediators implicated in the AC/cyclic AMP pathway. With this purpose, we overexpressed AC1 in the human pancreatic adenocarcinoma (HPAC) cell line, and through the protein kinase A (PKA) inhibitor H-89 and the exchange protein directly activated by cyclic AMP (EPAC) inhibitor ESI-09, we assessed the effector involved upon the treatment with forskolin. In a previous study, we showed that PKA alone mediates the inhibitory effect of forskolin/AC1/cyclic AMP on proliferation of HPAC cells. In the present study, we examined the effectors implicated in the AC1 inhibitory effect on cell migration through utilization of the CytoSelect 24-well cell migration assay kit. Our current experimental data suggests that PKA and EPAC are both likely to be downstream mediators in the effect of forskolin/AC1/cyclic AMP on migration of HPAC cells.