Nicotinic receptor‐associated modulation of stimulatory and inhibitory neurotransmitters in NNK‐induced adenocarcinoma of the lungs and pancreas |
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Authors: | Hussein AN Al‐Wadei Hildegard M Schuller |
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Affiliation: | 1. Experimental Oncology Laboratory, Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, TN, USA;2. Sana'a University, Sana'a, Yemen |
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Abstract: | Small airway‐derived pulmonary adenocarcinoma (PAC) and pancreatic ductal adenocarcinoma (PDAC) are among the most common human cancers and smoking is a risk factor for both. Emerging research has identified cAMP signalling stimulated by the stress neurotransmitters adrenaline and noradrenaline as an important stimulator of adenocarcinomas, including PAC and PDAC. The nicotine‐derived nitrosamine 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK) is a potent mutagen and the most powerful tobacco carcinogen. NNK is also an agonist for nicotinic acetylcholine receptors (nAChRs). Using hamster models of NNK‐induced PAC and PDAC, we have tested the hypothesis that in analogy to chronic effects of nicotine in the brain, NNK may modulate the α7‐ and α4β2nAChRs, causing an increase in stress neurotransmitters and a decrease in the inhibitory neurotransmitter γ‐aminobutyric acid (GABA). Immunoassays showed a significant increase in serum adrenaline/noradrenaline and increased intracellular cAMP in the cellular fraction of blood of NNK‐treated hamsters. Western blots on microdissected control small airway epithelia, alveolar epithelia, pancreatic islet and pancreatic duct epithelia, and from NNK‐induced PACs and PDACs showed that the GABA‐synthesizing enzyme glutamate decarboxylase 65 (GAD65) and GABA were suppressed in NNK‐induced PACs and PDACs. In contrast, protein expression of the α7nAChR, α4nAChR as well as p‐CREB and p‐ERK1/2 were up‐regulated. These findings suggest that NNK‐induced alterations in regulatory nAChRs may contribute to the development of smoking‐associated PAC and PDAC by disturbing the balance between cancer‐stimulating and ‐inhibiting neurotransmitters. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. |
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Keywords: | NNK‐induced PAC NNK‐induced PDAC nicotinic acetylcholine receptor stress neurotransmitters GABA |
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