ToxSci Advance Access originally published online on September 16, 2008
Toxicological Sciences 2008 106(2):364-375; doi:10.1093/toxsci/kfn195
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Gaseous Nitrogen Oxide Promotes Human Lung Cancer Cell Line A549 Migration, Invasion, and Metastasis via iNOS-Mediated MMP-2 Production
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* Graduate Institute of Biological Science and Technology, College of Medicine and Life Science, Chung Hwa University of Medical Technology, Tainan, Taiwan
School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
Department of Medical Technology, College of Medicine and Life Science, Chung Hwa University of Medical Technology, Tainan, Taiwan
¶ Department of Pathology, Chung Shan Medical University Hospital, Taichung, Taiwan
Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
1 To whom correspondence should be addressed at Institute of Biochemistry and Biotechnology, Chung Shan Medical University, No. 110, Sec. 1, Chien Kuo N. Road, Taichung 402, Taiwan. Fax: +886-4-23248167. E-mail: wcj{at}csmu.edu.tw.
Received May 10, 2008; accepted September 2, 2008
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Abstract |
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Gaseous nitrogen oxide (gNO) is an important indoor and outdoor air pollutant. Many studies have indicated gNO causes lung tissue damage by its oxidation properties and free radicals. However, there are considerably few data on the association between lung cancer and gNO exposure. The purpose of this study was to examine whether gNO could contribute to the process of malignant progression of lung cancer. The results of wound-healing assay and in vitro transwell assay revealed that gNO-induced dose and time dependently the migration and invasion of A549 cells, a human lung cancer cell line, under noncytotoxic concentrations. gNO was able to induce release of NO from A549 cells, an effect that was mediated via the activation of inducible nitric oxide synthases (iNOS), but not constitutive isoforms, during the same treatment period. An increased expression of matrix metalloproteinase (MMP) and a coincided reduction in repress tissue inhibitors of metalloprotease-2 were observed upon the treatment of gNO. The gNO-mediated MMP-2 induction appeared to be a consequence of nuclear factor kappa B and activation protein-1 activation, because that their DNA binding activity was enhanced by gNO. All these influences of gNO were efficiently repressed by the pretreatment of a NOS inhibitor (NG-nitro-L-arginine methyl ester). Using a mouse model, we showed that gNO promoted A549 metastasis to the lung through a mechanism involving the iNOS-dependent MMP-2 activity. Our data imply that gNO exposure, which in turn led to iNOS activation and the enhancement of MMP-mediated cellular events, was related to lung cancer development.
Key Words: gaseous nitrogen oxide; malignant progression; human lung cancer A549 cells; inducible nitric oxide synthases; matrix metalloproteinase; tissue inhibitors of metalloprotease-2; NG-nitro-L-arginine methyl ester.