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[Cancer Research 61, 1791-1795, March 1, 2001]
© 2001 American Association for Cancer Research

Advances in Brief

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

Arti Shukla, Cynthia R. Timblin, Andrea K. Hubbard, Jonathan Bravman and Brooke T. Mossman2

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 {alpha}-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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