Silica-induced activation of c-Jun-NH2-terminal amino kinases, protracted expression of the activator protein-1 proto-oncogene, fra-1, and S-phase alterations are mediated via oxidative stress.
Crystalline silica has been classified as a group 1 human carcinogen in the lung. However, its mechanisms of action on pulmonary epithelial cells which give rise to lung cancers are unclear. Using a nontransformed alveolar type II epithelial cell line (C10), we show that alpha-quartz silica causes persistent dose-related increases in phosphorylation of c-Jun-NH2-terminal amino kinases (JNKs) that are inhibited by antioxidants (P < or = 0.05). Increases in activator protein-1 (AP-1) binding to DNA and transactivation of AP-1-dependent gene expression by silica were accompanied by increases in steady-state mRNA levels of the AP-1 family members, c-jun, junB, fra-1, and c-fos at 8 h and elevated mRNA levels of fra-1 at 24 h (P < or = 0.05). Addition of tetramethylthiourea inhibited silica-associated increases infra-1 and proportions of cells in S-phase (P < or = .05). Our findings indicate that silica induces JNK activity, AP-1-dependent gene expression, ie., fra-1, and DNA synthesis via oxidative stress. Moreover, they suggest that silica may act mechanistically as a mitogen or tumor promoter, rather than a genotoxic carcinogen, in the development of lung cancers.
Department of Pathology, University of Vermont College of Medicine, Burlington 05405, USA.
A
A
Shukla
C R
CR
Timblin
A K
AK
Hubbard
J
J
Bravman
B T
BT
Mossman
D000818:Animals; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D017665:Hydroxyl Radical / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis* / Q000235:genetics; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016196:S Phase / Q000187:drug effects*; D012822:Silicon Dioxide / Q000037:antagonists & inhibitors / Q000633:toxicity*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D000099169:Fos-Related Antigen 1
D004247:DNA; D016166:Free Radical Scavengers; D017665:Hydroxyl Radical; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D012822:Silicon Dioxide; D013890:Thiourea; D018808:Transcription Factor AP-1; D000099169:Fos-Related Antigen 1; C000715470:MAS1 protein, human; C019107:tetramethylthiourea