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Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality in Western countries and smoking, diabetes, and pancreatitis are risk factors. The prognosis of this cancer is extremely poor due to its resistance to available therapies and extensive metastasis. We have shown that beta-adrenergic neurotransmitter receptors (beta-ARs) regulate the growth of human PDAC cell lines and their cells of origin, pancreatic duct epithelia, via adenylate cyclasecAMPPKA CREB and transactivation the EGFR pathway. Based on these findings, we hypothesize that inhibition of beta-adrenergic neurotransmitter signaling can be utilized for the prevention of PDAC. Our data show that beta-adrenergic signaling increased cell migration while inhibiting starvation-induced caspase 3 expression. The physiological agonist for beta-adrenoreceptors, noradrenalin, and activated PKA were overexpressed in human PDAC tissue microarrays whereas the inhibitory neurotransmitter gammma-aminubutyric acid (GABA) was underexpressed in most PDACs. The beta-blocker propranolol and dietary inhibition of pancreatitis had strong cancer preventive effects in a hamster model of pancreatitis-associated PDAC. GABA and the antagonist for GABAB receptors, baclophen, inhibited the beta-AR-mediated stimulation of PDAC cell proliferation and migration. GABA or baclofen inhibited isoproterenol-induced cAMP signaling below base levels. ERK1/2 activity in response to isoproterenol was blocked by GABA, an effect enhanced by transient overexpression of the GABABR and abolished by GABABR knockdown. The chronic fibro-inflammatory disease pancreatitis destroys most pancreatic islets, which are the principal source of GABA in the pancreas. As suggested by our data, the resulting reduction in pancreatic GABA may increase the risk for the development of PDAC, particularly when stimulatory beta-AR signaling is simultaneously enhanced. Inhibition of stimulatory beta-AR signaling by pharmacological antagonists or by restoration of inhibitory GABA signaling may thus be promising targets for the prevention of pancreatitis-associated PDAC. Stimulation of the GABABR by GABA or baclofen inhibited isoproterenol-induced cAMP signaling below base levels. ERK1/2 activity in response to isoproterenol was blocked by GABA, an effect enhanced by transient overexpression of the GABABR and abolished by GABABR knockdown.
 Supported by RO1 CA042829 with the National Cancer Institute and the State of Tennessee’s Center of Excellence Program.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA