Abstract
Abstract
Nicotine addiction is characterized by changes of nicotinic acetylcholine receptors (nAChRs) in the brain to increase the production of excitatory neurotransmitters noradrenaline/adrenaline while reducing inhibitory neurotransmitter γ-aminobutyric acid (GABA). We tested the hypothesis that nAChR-regulated neurotransmitters regulate lung adenocarcinoma (AC) and that nAChR changes in AC cells analogous to nicotine addiction in the brain contribute to the development and progression of this cancer.
Mice carrying xenografts of the human AC cell line NCI-H322 received no treatment or were given nicotine in the drinking water for 30 days with and without intraperitoneal injections of GABA. Xenograft sizes were measured. Noradrenaline and adrenaline in serum and cAMP in blood cells and tumor cells were measured by immunoassays. Protein expression of α7nAChR, α4β2nAChR, p-CREB, p-ERK1/2, glutamate decarboxylase 65 (GAD65) and GABA in xenografts were analyzed by Western blotting. Nicotine increased xenograft sizes and upregulated receptor protein of both nAChRs in xenografts while increasing noradrenaline, adrenaline and cAMP in the blood. Xenograft expression of GAD65 and GABA were suppressed by nicotine while p-CREB, p-ERK and cAMP were induced. GABA reversed all these effects of nicotine. In vitro exposure of AC cells for 7 days to nicotine upregulated and sensitized the α7nAChR, resulting in a significant increase in noradrenaline/adrenaline production in response to agonist and enhancement of its cAMP-dependent signaling responses. At the same time, the α4nAChR was desensitized by chronic nicotine causing a significant reduction in GABA production.
Nicotine-induced predominance of stimulatory noradrenaline and deficiency in inhibitory GABA in AC cells analogues to the nicotine addicted brain may therefore contribute to the development and progression of AC in smokers and GABA may be useful for the marker-guided prevention and adjuvant therapy of AC.
Supported by a grant from the National Lung Cancer Partnership and LUNGevity Foundation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3231.