Small airway-derived pulmonary adenocarcinoma (PAC) and pancreatic ductal adenocarcinoma (PDAC) are common human cancers and smoking is a risk factor for both. Emerging research has identified cAMP signaling stimulated by the stress neurotransmitters adrenaline and noradrenaline as stimulators of PAC and PDAC. We have shown that the inhibitory neurotransmitter \#947;-aminobutyric acid (GABA) blocks the cAMP-dependent proliferation and migration of PAC and PDAC cells in vitro. The nicotine-derived nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent mutagen and carcinogen. NNK is also an agonist for nicotinic acetylcholine receptors (nAChRs). These receptors are central regulators that control the synthesis and release of neurotransmitters, growth factors, angiogenic factors and inflammatory mediators. The alpha7-nAChR stimulates the synthesis and release of adrenaline and noradrenaline in the brain and from nerve endings in all organs and tissues. The alpha4beta2-nAChR stimulates the synthesis and release of GABA that is expressed in most mammalian cells. While signal transduction events downstream of nAChRs expressed in cancer cells have been extensively studied, the systemic effects of these receptors on cancer have been largely ignored. 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 alpha7 and alpha4beta2-nAChR, causing a systemic increase in stress neurotransmitters and decrease in GABA. In support of our hypothesis, we found significant increase in serum adrenaline/noradrenaline and increased cAMP in the cellular fraction of blood from NNK treated hamsters. The GABA synthesizing enzyme glutamate decaboxylase 65 (GAD65) and GABA were suppressed in NNK-induced PACs and PDACs, whereas protein expression of the alpha7nAChR, alpha4-nAChR as well as p-CREB and p-ERK1/2 were upregulated. In analogy to the chronic effects of nicotine on brain cells, these data suggest that chronic exposure to NNK upregulates both investigated nAChRs while additionally desensitizing the alpha4beta2-nAChR, resulting in increased levels of cancer stimulating stress neurotransmitters and suppressed inhibitory GABA. Collectively, these findings suggest, for the first time, that NNK-induced alterations in regulatory nAChRs may contribute to the development of smoking-associated PAC and PDAC by disturbing the systemic balance between cancer stimulating and inhibiting neurotransmitters.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2507.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO