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Differential Effects of Bryostatins and Phorbol Esters on Arachidonic Acid Metabolite Release and Epidermal Growth Factor Binding in C3H 10T Cells¹

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

The bryostatins, a group of macrocyclic lactones isolated on the basis of their antineoplastic activity, activate protein kinase C in vitro and block phorbol ester binding to this enzyme. In some cellular systems, bryostatins mimic phorbol ester action. In other systems, however, the bryostatins display only marginal agonistic action and, instead, inhibit phorbol ester-induced responses. At least in primary mouse epidermal cells, a transient duration of action of bryostatin 1 could rationalize these differences. To determine whether this model of transient activation could explain the dual actions of bryostatin 1 in other cell systems, we have examined the effects of bryostatin 1 on short-term responses in C3H 10T mouse fibroblasts. Even at very short exposures (30 min), bryostatin 1 blocked phorbol ester-induced arachidonic acid metabolite release and induced only minimal release when assayed alone. In contrast, epidermal growth factor binding was markedly and rapidly decreased in bryostatin 1-treated C3H 10T cells, and this decrease showed only limited reversal 16 h after initial exposure. Bryostatins 2, 3, 4, 10, and several of their derivatives caused variable arachidonic acid metabolite release (10 to 60% of phorbol ester control) and correspondingly variable inhibition of phorbol ester action. Our findings on arachidonic acid metabolite release argue against transient activation of the protein kinase C pathway as the sole explanation of bryostatin 1 action. They indicate, moreover, differences in the structure-activity relations of the bryostatins for the phorbol ester-mimetic and phorbol ester-inhibitory actions.

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 USPHS Grants Ca-16049-07 to 11 awarded by the National Cancer Institute, Department of Health and Human Services.

² Supported by the Pharmacology Research Associate Program of the National Institute of General Medical Sciences, NIH.

³ To whom requests for reprints should be addressed.

Received 11/ 6/87. Revised 3/18/88. Accepted 3/24/88.

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