Gaseous nitrogen oxide promotes human lung cancer cell line A549 migration, invasion, and metastasis via iNOS-mediated MMP-2 production.
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 (N(G)-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.
Chen
Jing-Hsien
JH
Graduate Institute of Biological Science and Technology, College of Medicine and Life Science, Chung Hwa University of Medical Technology, Tainan, Taiwan.
Lin
Hui-Hsuan
HH
Chiang
Tai-An
TA
Hsu
Jeng-Dong
JD
Ho
Hsieh-Hsun
HH
Lee
Yi-Chieh
YC
Wang
Chau-Jong
CJ
D001483:Base Sequence; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D003470:Culture Media; D017931:DNA Primers; D005740:Gases; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D009589:Nitrogen Oxides / Q000494:pharmacology*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D003470:Culture Media; D017931:DNA Primers; D005740:Gases; D016328:NF-kappa B; D009589:Nitrogen Oxides; D016755:Proto-Oncogene Proteins c-jun; D052247:Nitric Oxide Synthase Type II; D020778:Matrix Metalloproteinase 2