title: NNK promotes migration and invasion of lung cancer cells through activation of c-Src/PKCι/FAK loop.
abstract: Cigarette smoking, either active or passive, is the most important risk factor in the development of human lung cancer. Mounting evidence indicates that cigarette smoke constituents not only contribute to tumorigenesis but also may increase the spread of cancer in the body. Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is formed by nitrosation of nicotine and has been identified as the most potent carcinogen. NNK, an important component in cigarette smoke, may also promote tumor metastasis by regulating cell motility. Here we found that NNK can induce activation of a functionally interdependent protein kinase cascade, including c-Src, PKCι and FAK, in association with increased migration and invasion of human lung cancer cells. c-Src, PKCι and FAK are extensively co-localized in the cytoplasm. Treatment of cells with α(7) nAChR specific inhibitor α-bungarotoxin (α-BTX) blocks NNK-stimulated activation of c-Src, PKCι and FAK and suppresses cell migration and invasion. Intriguingly, NNK enhances c-Src/PKCι and PKCι/FAK bindings, indicating a potential mechanism by which these kinases activate each other. Specific disruption of c-Src, PKCι or FAK expression by RNA interference significantly reduces NNK-induced cell migration and invasion. These findings suggest that NNK-induced migration and invasion may occur in a mechanism through activation of a c-Src/PKCι/FAK loop, which can contribute to metastasis and/or development of human lung cancer.
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine, Winship Cancer Institute of Emory University, Atlanta, GA 30322, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.forename: Lijun
authors.initials: L
authors.lastname: Xu
authors.forename: Taofeek K
authors.initials: TK
authors.lastname: Owonikoko
authors.forename: Shi-Yong
authors.initials: SY
authors.lastname: Sun
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Curran
authors.forename: Xingming
authors.initials: X
authors.lastname: Deng
mesh_terms: D015153:Blotting, Western; D002038:Bungarotoxins / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009602:Nitrosamines / Q000494:pharmacology*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014945:Wound Healing / Q000187:drug effects; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000099293:Protein Kinase C-lambda
chemical_list: D002038:Bungarotoxins; D002273:Carcinogens; D051417:Focal Adhesion Kinase 1; D007527:Isoenzymes; D009602:Nitrosamines; D011493:Protein Kinase C; D016392:Proto-Oncogene Proteins pp60(c-src); D034741:RNA, Small Interfering; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000099293:Protein Kinase C-lambda; C579167:Chrna7 protein, human; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C496050:PTK2 protein, human