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      Role of alpha7-nicotinic acetylcholine receptor in human non-small cell lung cancer proliferation.

      Cell Proliferation

      alpha7 Nicotinic Acetylcholine Receptor, Xenograft Model Antitumor Assays, pharmacology, Tubocurarine, metabolism, Ribosomal Protein S6 Kinases, 90-kDa, genetics, Receptors, Nicotinic, Proto-Oncogene Proteins c-raf, Nicotine, Models, Biological, Mice, SCID, Mice, Male, pathology, enzymology, Lung Neoplasms, Ligands, Humans, drug effects, Gene Expression Regulation, Neoplastic, Female, Extracellular Signal-Regulated MAP Kinases, Enzyme Activation, Cobra Neurotoxin Proteins, Cell Proliferation, Cell Line, Tumor, Carcinoma, Non-Small-Cell Lung, Bungarotoxins, Apoptosis, Animals

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          Abstract

          Lung cancer is the most common cause of cancer death in the world. Cigarette smoking represents the major risk factor. Nicotine, an active component of cigarettes, can induce cell proliferation, angiogenesis and apoptosis resistance. All these events are mediated through the nicotinic acetylcholine receptor (nAChR) expressed on lung cancer cells. We speculate that new insights into the pathophysiological roles of nAChR may lead to new therapeutic avenues to reduce non-small cell lung cancer (NSCLC) tumour growth. Human samples of NSCLC, cell lines and mouse models were utilized in Western blotting, reverse transcriptase polymerase chain reaction and apoptosis studies. Human NSCLC tissues expressed alpha7-nAChR. This expression was higher in smoking patients with squamous carcinomas than those with adenocarcinomas and in male smoking patients than in females. All the data support the hypothesis that major expression of alpha7-nAChR is related to major activation of the Rb-Raf-1/phospho-ERK/phospho-p90RSK pathway. alpha7-nAChR antagonists, via mitochondria associated apoptosis, inhibited proliferation of human NSCLC primary and established cells. Nicotine stimulates tumour growth in a murine model, A549 cells orthotopically grafted. The effects of nicotine were associated with increases in phospho-ERK in tumours. Proliferation effects of nicotine could be blocked by inhibition of alpha7-nAChR by the high affinity ligand alpha-cobratoxin. These results showed that alpha7-nAChR plays an important role in NSCLC cell growth and tumour progression as well as in cell death.

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          Author and article information

          Journal
          19040571
          10.1111/j.1365-2184.2008.00566.x

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