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Article
Nicotinic receptor-associated modulation of stimulatory and inhibitory neurotransmitters in NNK-induced adenocarcinoma of the lungs and pancreas
Journal of Pathology (2009)
  • Hussein Abdulhadi Nasser Al-Wadei, University of Tennessee, Knoxville
  • Hildegard M Schuller, University of Tennessee - Knoxville
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 alpha(7)- and alpha(4)beta(2)nAChRs, causing an increase in stress neurotransmitters and a decrease in the inhibitory neurotransmitter gamma-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 alpha(7)nAChR, alpha(4)nAChR 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.

Keywords
  • NNK-induced PAC,
  • NNK-induced PDAC,
  • nicotinic acetylcholine receptor,
  • stress neurotransmitters,
  • GABA
Publication Date
2009
Citation Information
Hussein Abdulhadi Nasser Al-Wadei and Hildegard M Schuller. "Nicotinic receptor-associated modulation of stimulatory and inhibitory neurotransmitters in NNK-induced adenocarcinoma of the lungs and pancreas" Journal of Pathology Vol. 218 Iss. 4 (2009)
Available at: http://works.bepress.com/hussein_al-wadei/5/