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Contrasting Duration of Inhibition of Cell-Cell Communication in Primary Mouse Epidermal Cells by Phorbol 12,13-Dibutyrate and by Bryostatin 1¹

Molecular Mechanisms of Tumor Promotion Section [G. P., E. R., P. M. B.] and In Vitro Pathogenesis Section [S. H. Y.], Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, Maryland 20892 and Cancer Research Institute and Department of Chemistry [C. L. H., G. R. P.], Arizona State University, Tempe, Arizona 85287

The bryostatins, macrocyclic lactones isolated on the basis of their antineoplastic activity, activate protein kinase C in vitro and inhibit phorbol ester binding to the enzyme. In intact cells, the bryostatins induce some phorbol ester responses, such as neutrophil activation, but paradoxically they not only fail to induce other responses, e.g., differentiation in HL-60 promyelocytic leukemia cells, but actually block response to the phorbol esters. We compare here bryostatin 1 and phorbol 12,13-dibutyrate as inhibitors of cell-cell communication in cultured primary mouse epidermal cells. Like phorbol 12,13-dibutyrate, bryostatin 1 at nanomolar concentrations markedly inhibited cell coupling. It differed from the phorbol esters, however, in that its action was more transient. By 4 h of incubation bryostatin 1 caused little inhibition of coupling. Moreover, coincubation of bryostatin 1 and phorbol 12,13-dibutyrate gave no greater response at this time than that found for bryostatin 1 alone. Time-dependent inhibition of the protein kinase C pathway could account for many of the observed differences between the actions of the phorbol esters and bryostatin 1.

¹ The Arizona State University Cancer Research Institute laboratory received financial support from the Fannie E. Rippel Foundation, the Arizona Disease Control Research Commission, the Robert B. Dalton Endowment Fund, and Public Health Service Grant CA-16049-07-11 awarded by the National Cancer Institute, Department of Health and Human Services.

² Current address: Department of Hygiene and Epidemiology, University Medical School, Nagyerdei Krt. 98, H-4012, Debrecen, Hungary.

³ To whom requests for reprints should be addressed.

Received 7/28/87. Revised 10/13/87. Accepted 10/15/87.

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