Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality with near 100% of the victims succumbing within 6 month of diagnosis. New strategies for PDAC prevention are therefore urgently needed. Using two risk factors for PDAC (pancreatitis and smoking), we have established a hamster model of PDAC by inducing pancreatitis in the animals via ethanol in the drinking water while additionally injecting them with the nicotine-derived carcinogenic nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK). Using this animal model as well as xenografts from human PDAC in mice and in vitro studies with human PDAC cell lines and the putative cell of origin of PDAC, pancreatic duct epithelial cells, our published and new preliminary data show that adenylyl cyclase-dependent intracellular signaling downstream of beta-adrenoreceptors (b-ARs) stimulates PDAC while additionally triggering the release of epidermal growth factor, vascular endothelial growth factor and arachidonic acid. NNK activates this signaling pathway directly by binding to b-ARs and indirectly by stimulating the a7nicotinic acetylcholine receptor (a7nAChR)-mediated release of the stress neurotransmitters noradrenaline and adrenaline, which are agonists for b-ARs. All components of this stimulatory network are upregulated in PDAC while at the same time g-aminobutyric acid (GABA) which inhibits this pathway by blocking the activation of adenylyl cyclase is suppressed. Treatment of PDAC cells in vitro or PDAC xenografts in vivo with GABA had inhibiting effects. These findings suggest GABA as a potential PDAC preventive agent. To test this hypothesis and at the same time further our understanding on the regulation of PDAC by stimulatory b-AR signaling and inhibitory GABA signaling we propose four specific aims.
Specific Aim 1 : Using our hamster model, we will test the hypothesis that GABA or the synthetic GABA analogue baclophen prevent the development of PDAC.
Specific Aim 2 : Using PCR microarrays, Western blotting and immunohistochemistry, we will investigate the modulation of markers for proliferation, angiogenesis, metastasis, apoptosis, cell renewal, and cAMP signaling by GABA in tissues from hamster PDAC and normal pancreatic tissue.
Specific Aim 3 : Using human PDAC cell lines and pancreatic duct epithelial cells in vitro, we will determine the inhibitory actions of GABA in b-AR and PGE2-mediated signaling pathways and explore a potential reduction in TNFa and IL-1b by GABA.
Specific Aim 4 : We will test the hypothesis that inhibited GABA production due to NNK-induced desensitization of the a4nAChR and stimulation of stress neurotransmitter production due to NNK-induced upregulation of the a7nAChR contribute to the stimulation of PDAC. Data generated will provide a preclinical basis for the use of GABA in the prevention of PDAC.

Public Health Relevance

Pancreatic cancer is the fourth leading cause of cancer death with a mortality near 100% within one year of diagnosis because it does not respond to existing therapies and metastasizes extensively. New strategies to combat this deadly disease are thus urgently needed. Data presented in this project along with known biological effects of risk factors for pancreatic cancer (smoking, diabetes, pancreatitis) suggest that hyperactive beta-adrenoreceptors and possibly other G-protein coupled receptors stimulate pancreatic cancer development and progression while at the same time the pancreatic production of gamma-aminobutyric acid (GABA), which normally controls the activity of these receptors via activation of the inhibitory GABAB receptor, is reduced. Based on this novel concept, we propose to restore deficient pancreatic GABA for the prevention of pancreatic cancer. In vitro and in vivo studies proposed under this project will provide a preclinical basis for the use of GABA-ergic agents for the marker-guided prevention of pancreatic cancer in individuals with pancreatic GABA deficiency.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Chemo/Dietary Prevention Study Section (CDP)
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Seifried, Harold E
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University of Tennessee Knoxville
Schools of Veterinary Medicine
United States
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Banerjee, Jheelam; Papu John, Arokya M S; Al-Wadei, Mohammed H et al. (2016) Prevention of pancreatic cancer in a hamster model by cAMP decrease. Oncotarget 7:44430-44441
Al-Wadei, Mohammed H; Banerjee, Jheelam; Al-Wadei, Hussein A N et al. (2016) Nicotine induces self-renewal of pancreatic cancer stem cells via neurotransmitter-driven activation of sonic hedgehog signalling. Eur J Cancer 52:188-96
Banerjee, Jheelam; Al-Wadei, Hussein An; Al-Wadei, Mohammed H et al. (2014) Differential modulation of nicotine-induced gemcitabine resistance by GABA receptor agonists in pancreatic cancer cell xenografts and in vitro. BMC Cancer 14:725
Al-Wadei, Mohammed H; Al-Wadei, Hussein A N; Schuller, Hildegard M (2013) Gamma-amino butyric acid (GABA) prevents the induction of nicotinic receptor-regulated signaling by chronic ethanol in pancreatic cancer cells and normal duct epithelia. Cancer Prev Res (Phila) 6:139-48
Schuller, Hildegard M (2013) Effects of tobacco constituents and psychological stress on the beta-adrenergic regulation of non-small cell lung cancer and pancreatic cancer: implications for intervention. Cancer Biomark 13:133-44
Banerjee, Jheelam; Al-Wadei, Hussein A N; Schuller, Hildegard M (2013) Chronic nicotine inhibits the therapeutic effects of gemcitabine on pancreatic cancer in vitro and in mouse xenografts. Eur J Cancer 49:1152-8
Schuller, Hildegard M; Al-Wadei, Hussein A N (2012) Beta-adrenergic signaling in the development and progression of pulmonary and pancreatic adenocarcinoma. Curr Cancer Ther Rev 8:116-127
Al-Wadei, Mohammed H; Al-Wadei, Hussein A N; Schuller, Hildegard M (2012) Effects of chronic nicotine on the autocrine regulation of pancreatic cancer cells and pancreatic duct epithelial cells by stimulatory and inhibitory neurotransmitters. Carcinogenesis 33:1745-53
Al-Wadei, Mohammed H; Al-Wadei, Hussein A N; Schuller, Hildegard M (2012) Pancreatic cancer cells and normal pancreatic duct epithelial cells express an autocrine catecholamine loop that is activated by nicotinic acetylcholine receptors ýý3, ýý5, and ýý7. Mol Cancer Res 10:239-49
Al-Wadei, Hussein A N; Al-Wadei, Mohammed H; Ullah, Mohammad F et al. (2012) Celecoxib and GABA cooperatively prevent the progression of pancreatic cancer in vitro and in xenograft models of stress-free and stress-exposed mice. PLoS One 7:e43376

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