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 whic h give rise to lung cancers are unclear. Using a nontransformed alveolar ty pe II epithelial cell line (C10), we show that ru-quartz silica causes pers istent dose-related increases in phosphorylation of c-Jun-NH2-terminal amin o kinases (JNKs) that are inhibited by antioxidants (P less than or equal t o 0.05). Increases in activator protein-1 (AP-1) binding to DNA and transac tivation of AP-1-dependent gene expression by silica were accompanied by in creases 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 less t han or equal to 0.05). Addition of tetramethylthiourea inhibited silica-ass ociated increases in fra-1 and proportions of cells in S-phase (P less than or equal to .05), Our findings indicate that silica induces JNK activity, AP-1-dependent gene expression, i.p., fra-1, and DNA synthesis via oxidativ e stress. Moreover, they suggest that silica may act mechanistically as a m itogen or tumor promoter, rather than a genotoxic carcinogen, in the develo pment of lung cancers.