cooperative regulation of non-small cell lung carcinoma by nicotinic and beta-adrenergic receptors a novel target for intervention合作监管烟碱和该项受体非小细胞肺癌的一种新颖的目标干预.pdf

Cooperative Regulation of Non-Small Cell Lung Carcinoma by Nicotinic and Beta-Adrenergic Receptors: A Novel Target for Intervention 1,2 1 1 Hussein A. N. Al-Wadei , Mohammed H. Al-Wadei , Hildegard M. Schuller * 1 Experimental Oncology Laboratory, Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee, United States of America, 2 Department of Preventive Medicine, Sana’a University, Sana’a, Yemen Abstract Lung cancer is the leading cause of cancer death; 80–85% of lung cancer cases are non-small cell lung cancer (NSCLC). Smoking is a documented risk factor for the development of this cancer. Although nicotine does not have the ability to initiate carcinogenic events, recent studies have implicated nicotine in growth stimulation of NSCLC. Using three NSCLC cell lines (NCI-H322, NCI-H441 and NCI-H1299), we identified the cooperation of nicotinic acetylcholine receptors (nAChRs) and b-adrenergic receptors (b-ARs) as principal regulators of these effects. Proliferation was measured by thymidine incorporation and MTT assays, and Western blots were used to monitor the upregulation of the nAChRs and activation of signaling molecules. Noradrenaline and GABA were measured by immunoassays. Nicotine-treated NSCLC cells showed significant induction of the a7nAChR and a4nAChR, along with significant inductions of p-CREB and p-ERK1/2 accompanied by increases in the stress neurotransmitter noradrenaline, which in turn led to the observed increase in DNA synthesis and cell proliferation. Effects on cell proliferation and signaling proteins were reversed by the a7nAChR antagonist a-BTX or the b-blocker propranolol. Nicotine treatment also down-r