4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) enhances invasiveness of lung cancer cells by up-regulating contactin-1 via the alpha7 nicotinic acetylcholine receptor/ERK signaling pathway.
Tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) exhibits potent carcinogenic activity in vitro and in vivo and has been shown to contribute to multiple steps in the tumorigenesis of lung cancer. In this study, we found that NNK up-regulated the expression of contactin-1, a cell adhesion molecule which has been implicated in cell migration, in lowly invasive CL1.0 lung cancer cells in a dose-dependent manner. Reverse transcription-polymerase chain reaction (RT-PCR) analysis and promoter activity assay suggested that NNK directly stimulated contactin-1 gene transcription. Block of alpha7 nicotinic acetylcholine receptor (nAChR) by alpha-bungarotoxin attenuated NNK-induced increase of contactin-1. We also found that NNK activated alpha7 nAChR downstream AKT and extracellular signal-regulated kinase (ERK) signaling pathways in CL1.0 cells. However, only ERK signaling pathway inhibitor PD98059, but not AKT signaling pathway inhibitor LY294002, suppressed the induction of contactin-1 by NNK. Up-regulation of contactin-1 by NNK increased adhesive and invasive abilities of CL1.0 cells which could be effectively inhibited by contactin-1 neutralizing antibody, alpha-bungarotoxin and PD98059. Taken together, we conclude that contactin-1 is a molecule mediator for NNK to promote invasiveness of lung cancer cells.
Hung
Yu-Hsuan
YH
Department of Life Science, National Dong Hwa University, Hualien, Taiwan, ROC.
Hung
Wen-Chun
WC
D002038:Bungarotoxins / Q000494:pharmacology; D015816:Cell Adhesion Molecules, Neuronal / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D058967:Contactin 1; D058966:Contactins; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009602:Nitrosamines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects; D064569:alpha7 Nicotinic Acetylcholine Receptor
D002038:Bungarotoxins; C548669:CNTN1 protein, human; D015816:Cell Adhesion Molecules, Neuronal; C579167:Chrna7 protein, human; D058967:Contactin 1; D058966:Contactins; D005419:Flavonoids; D009602:Nitrosamines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one