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Inhibition of Protein Kinase C Prevents Asbestos-induced c-fos and c-jun Proto-Oncogene Expression in Mesothelial Cells¹

Departments of Pathology [H. F., T. R. Q., Y. M. W. J., C. R. T., J. P. M., N. H. H., D. J. T., B. T. M.] and Biostatistics [P. V.], University of Vermont, Burlington, Vermont 05405, and W. Alton Jones Cell Science Center, Inc., Lake Placid, New York 12946 [S. J.]

Asbestos and the phorbol ester tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), increase c-fos and c-jun mRNA levels and AP-1 DNA binding activity in rat pleural mesothelial (RPM) cells, a target cell of asbestos-induced mesotheliomas (N. H. Heintz et al., Proc. Natl. Acad. Sci. USA, 90: 3299-3303, 1993). Because protein kinase C (PKC) is the intracellular receptor of phorbol ester tumor promoters and asbestos is a putative tumor promoter in the respiratory tract, we hypothesized that PKC might play a critical role in asbestos-induced cell signaling pathways associated with regulation of proto-oncogenes. Using a panel of PKC antibodies, we identified PKC as the major PKC isozyme in RPM cells. We then pretreated cells with phorbol ester dibutyrate to down-modulate PKC or with calphostin C, a specific PKC inhibitor, to determine if depletion of PKC could block asbestos-induced c-fos/c-jun expression. Quantitation of Northern blots showed that fiber-associated c-fos/c-jun mRNA levels were significantly lower either after PKC down-modulation or pretreatment with calphostin C. In addition, to determine whether tyrosine kinases also were involved in proto-oncogene activation by asbestos, tyrphostin AG82 or herbimycin A was added to RPM cells before exposure to asbestos. These inhibitors decreased crocidolite-induced c-fos but not c-jun levels, suggesting that tyrosine kinases have different regulatory roles in asbestos-induced c-fos versus c-jun signaling pathways. The ability to block induction of asbestos-induced proto-oncogene expression using pharmacological intervention may be important in prevention and treatment of asbestos-induced proliferative diseases including lung cancers, mesothelioma, and pulmonary fibrosis.

¹ Supported by Grant ES 06499 from the National Institutes of Environmental Health Sciences and Grant HL 39469 from the National Heart, Lung and Blood Institute.

² To whom requests for reprints should be addressed.

Received 3/27/97. Accepted 6/12/97.

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