Induction of c-fos and c-jun Proto-oncogene Expression by Asbestos Is Ameliorated by A^-Acetyl-L-Cysteine in Mesothelial Cells1

Asbestos fibers cause dose-dependent, persistent increases in iiiKNA levels of c-jun and c-fos proto-oncogenes in rat pleural mesothelial (RPM) cells, the progenitor cells of asbestos-induced mesothelioma (N. Heintz, Y. M. W. Janssen, and B. T. Mossman. Proc. Nati. Acad. Sci. USA, 90: 3299-3303, 1993). Here we report that addition of ¿V-acetyl-L-cysteine decreases asbestos-mediated induction of c-fos and c-jun niKNA levels in a dose-dependent fashion. Exposure of RPM cells to asbestos causes depletion of total cellular glutathione, a response that can be abolished by pretreatment with JV-acetyl-L-cysteine. Pretreatment of cells with buthionine sulfoximine, an agent which diminishes glutathione pools, increases the magnitude of induction of c-fos and c-jun mRNA by asbestos. To determine whether asbestos-induced effects on proto-oncogene expression could be attributed to extracellular generation of active oxygen species (AOS), RPM cells were exposed to H,O, or xanthine and xanthine oxidase, a generating system of AOS. These oxidant stresses did not decrease cellular glutathione levels nor alter mRNA levels of c-fos or c-jun. How ever, increased mRNA levels of manganese-containing Superoxide dismutase and heme oxygenase were observed, indicating that RPM cells respond to AOS by increased expression of genes encoding antioxidant enzymes. These data indicate that the signaling pathways leading to c-fos/c-jun proto-oncogene induction by asbestos are not triggered directly by formation of extracellular AOS. However, intracellular thiol levels appear to influence the expression of c-fux and c-jun, suggesting a redoxsensitive component in the signaling cascade which modulates gene ex pression of c-fos and c-jun by asbestos.