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Contrasting Actions of Staurosporine, a Protein Kinase C Inhibitor, on Human Neutrophils and Primary Mouse Epidermal Cells

Molecular Mechanisms of Tumor Promotion Section [T. S., P. M. B.] and In Vitro Pathogenesis Section [S. H. Y.], Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, Maryland 20892; William B. Castle Hematology Research Laboratory, Boston City Hospital, and the Departments of Medicine and Pathology [A. I. T.], Boston University School of Medicine, Boston, Massachusetts 02118; and Research Department [A. Y. J.], Pharmaceutical Division, Ciba-Geigy Corporation, Summit, New Jersey 07901

Staurosporine, a recently described microbial alkaloid, is uniquely potent as an inhibitor of protein kinase C in vitro, being active at nM concentrations rather than the µM concentrations typical of other inhibitor classes. Like these other inhibitors, however, staurosporine exhibits only limited selectivity among different protein kinases. We report here that, in intact human neutrophils, nM concentrations of staurosporine blocked the action of the phorbol ester tumor promoters. In mouse primary epidermal cells, on the other hand, staurosporine failed to block the effects of phorbol 12,13-dibutyrate on epidermal growth factor binding and on induction of ornithine decarboxylase and epidermal transglutaminase. Unexpectedly, staurosporine induced morphological changes in keratinocytes to a dendritic shape resembling that induced by the phorbol esters. It also induced epidermal transglutaminase and cornified envelope production, markers of the differentiative pathway in the epidermal cells. We conclude that the effectiveness of staurosporine as a protein kinase C inhibitor in intact cells may depend markedly on the cell system. Other actions of staurosporine may predominate, and, in keratinocytes, its activity is suggestive of a tumor promoter rather than of an inhibitor of tumor promotion.

¹ Supported by Grants AI20064 and HL33565 from the NIH and by a grant from the Fairfax Hospital Association.

² To whom requests for reprints should be addressed.

Received 1/21/88. Revised 5/ 9/88. Accepted 5/13/88.

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