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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 Stress¹

Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont 05405 [A. S., C. R. T., J. B., B. T. M.], and University of Connecticut School of Pharmacy, Storrs Mansfield, Connecticut 06268 [A. K. H.]

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 -quartz silica causes persistent dose-related increases in phosphorylation of c-Jun-NH₂-terminal amino kinases (JNKs) that are inhibited by antioxidants (P 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 0.05). Addition of tetramethylthiourea inhibited silica-associated increases in fra-1 and proportions of cells in S-phase (P .05). Our findings indicate that silica induces JNK activity, AP-1-dependent gene expression, i.e., 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.

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