Nicotinic receptor-associated modulation of stimulatory and inhibitory neurotransmitters in NNK-induced adenocarcinoma of the lungs and pancreas.
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.
Al-Wadei
Hussein A N
HA
Experimental Oncology Laboratory, Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, TN, USA.
Schuller
Hildegard M
HM
D000230:Adenocarcinoma / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism; D006224:Cricetinae; D000242:Cyclic AMP / Q000032:analysis / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel / Q000379:methods; D004837:Epinephrine / Q000097:blood / Q000378:metabolism; D005260:Female; D008175:Lung Neoplasms / Q000378:metabolism*; D008297:Male; D008647:Mesocricetus; D023421:Models, Animal; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009602:Nitrosamines; D009638:Norepinephrine / Q000097:blood / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D011247:Pregnancy; D011978:Receptors, Nicotinic / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012907:Smoking / Q000009:adverse effects*; D005680:gamma-Aminobutyric Acid / Q000032:analysis / Q000378:metabolism
D018377:Neurotransmitter Agents; D009602:Nitrosamines; D011978:Receptors, Nicotinic; D005680:gamma-Aminobutyric Acid; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D000242:Cyclic AMP; D009638:Norepinephrine; D004837:Epinephrine