Search

Human lung adenocarcinoma (AC) and pancreatic ductal adenocarcinoma (PDAC) are among the most common types of human cancer and have a poor prognosis in all populations investigated. Smoking is a risk factor for both malignancies. Nicotine addiction is characterized by changes of nicotinic acetylcholine receptors (nAChRs) in the brain to increase the production of excitatory neurotransmitters while reducing inhibitory neurotransmitters. The current study has tested the hypothesis that chronic nicotine stimulates the growth of PAC and PDAC xenografts in nude mice via similar mechanisms. Groups of nude mice carrying xenografts of AC cell line NCI-H322 or PDAC cell line Panc-1 remained untreated, were given nicotine in the drinking water for 30 days in the presence and absence of daily injections with GABA or were treated with GABA alone. The diameters of xenografts were measured. Levels of noradrenaline and adrenaline, the stress hormone cortisol, the neurotransmitter γ-aminobutyric acid (GABA) in serum and xenograft tissues and levels of cAMP in the cellular fraction of blood and in xenograft tissue were assessed by immunoassays. The levels of GAD65, GAD67, nAChRs and signaling proteins downstream of β-ARs in the tumor tissue were determined by Western blotting. Our data show a significant stimulation of xenografts from both cell lines by chronic nicotine that was reversed by treatment with GABA. Nicotine also significantly increased the systemic levels of adrenaline, noradrenaline and cAMP while decreasing GABA. The protein levels of nicotinic acetylcholine receptors α4 and α7, p-CREB and p-ERK1/2 in the tumor tissue was significantly increased by nicotine and reversed by GABA. Nicotine additionally reduced the protein levels of both GAD isozymes in tumor tissue. In summary, our findings suggest that nicotine-induced predominance of stimulatory noradrenaline and deficiency in inhibitory GABA similar to nicotine-addiction in the brain may contribute to the development of lung adenocarcinoma in smokers and that GABA may be useful for marker-guided prevention and adjuvant therapy for PAC and PDAC. Supported by R01 CA042829 and R01 CA130888 with National Institutes of Health. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A6.