{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T02:24:21Z","timestamp":1788834261602,"version":"build-2803163510"},"reference-count":56,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2009,2,17]],"date-time":"2009-02-17T00:00:00Z","timestamp":1234828800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2009,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Small airway\u2010derived 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\u2010derived nitrosamine 4\u2010(methylnitrosamino)\u20101\u2010(3\u2010pyridyl)\u20101\u2010butanone (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\u2010induced PAC and PDAC, we have tested the hypothesis that in analogy to chronic effects of nicotine in the brain, NNK may modulate the \u03b1<jats:sub>7<\/jats:sub>\u2010 and \u03b1<jats:sub>4<\/jats:sub>\u03b2<jats:sub>2<\/jats:sub>nAChRs, causing an increase in stress neurotransmitters and a decrease in the inhibitory neurotransmitter \u03b3\u2010aminobutyric acid (GABA). Immunoassays showed a significant increase in serum adrenaline\/noradrenaline and increased intracellular cAMP in the cellular fraction of blood of NNK\u2010treated hamsters. Western blots on microdissected control small airway epithelia, alveolar epithelia, pancreatic islet and pancreatic duct epithelia, and from NNK\u2010induced PACs and PDACs showed that the GABA\u2010synthesizing enzyme glutamate decarboxylase 65 (GAD65) and GABA were suppressed in NNK\u2010induced PACs and PDACs. In contrast, protein expression of the \u03b1<jats:sub>7<\/jats:sub>nAChR, \u03b1<jats:sub>4<\/jats:sub>nAChR as well as p\u2010CREB and p\u2010ERK1\/2 were up\u2010regulated. These findings suggest that NNK\u2010induced alterations in regulatory nAChRs may contribute to the development of smoking\u2010associated PAC and PDAC by disturbing the balance between cancer\u2010stimulating and \u2010inhibiting neurotransmitters. Copyright \u00a9 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.2542","type":"journal-article","created":{"date-parts":[[2009,2,17]],"date-time":"2009-02-17T10:02:45Z","timestamp":1234864965000},"page":"437-445","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Nicotinic receptor\u2010associated modulation of stimulatory and inhibitory neurotransmitters in NNK\u2010induced adenocarcinoma of the lungs and pancreas"],"prefix":"10.1002","volume":"218","author":[{"given":"Hussein AN","family":"Al\u2010Wadei","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hildegard 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