INDUCTION OF C-FOS AND C-JUN PROTOONCOGENE EXPRESSION BY ASBESTOS IS AMELIORATED BY N-ACETYL-L-CYSTEINE IN MESOTHELIAL CELLS

Asbestos fibers cause dose-dependent, persistent increases in mRNA lev els of c-jun and c-fos proto-oncogenes in rat pleural mesothelial (RPM I) cells, the progenitor cells of asbestos-induced mesothelioma (N. H eintz, Y. M. W. Janssen, and B. T. Mossman. Proc. Natl. Acad. Sci. USA , 90: 3299-3303, 1993). Here we report that addition of N-acetyl-L-cys teine decreases asbestos-mediated induction of c-fos and c-jun mRNA le vels in a dose-dependent fashion. Exposure of RPM cells to asbestos ca uses depletion of total cellular glutathione, a response that can be a bolished by pretreatment with N-acetyl-L-cysteine. Pretreatment of cel ls 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-onco gene expression could be attributed to extracellular generation of act ive oxygen species (AOS), RPM cells were exposed to H2O2 or xanthine a nd xanthine oxidase, a generating system of AOS. These oxidant stresse s did not decrease cellular glutathione levels nor alter mRNA levels o f c-fos or c-jun. However, increased mRNA levels of manganese-containi ng superoxide dismutase and heme oxygenase were observed, indicating t hat 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 tr iggered directly by formation of extracellular AOS. However, intracell ular thiol levels appear to influence the expression of c-fos and c-ju n, suggesting a redox-sensitive component in the signaling cascade whi ch modulates gene expression of c-fos and c-jun by asbestos.