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Comparison of Effects of Bryostatins 1 and 2 and 12-O-Tetradecanoylphorbol-13-acetate on Protein Kinase C Activity in A549 Human Lung Carcinoma Cells¹

Cancer Research Campaign Experimental Chemotherapy Group, Pharmaceutical Sciences Institute, Aston University, Birmingham B4 7ET, England [I. L. D., T. D. B., A. G.], and Cancer Research Institute, Arizona State University, Tempe [G. R. P.], Arizona 85287

Activators of protein kinase C (PKC), such as 12-O-tetradecanoylphorbol-13-acetate (TPA) and bryostatins 1 and 2, inhibit the growth of A549 cells. At high concentrations the bryostatins do not affect cell growth. Here the hypothesis has been tested that modulation of A549 cell growth is the consequence of agent-induced changes in location or extent of cellular PKC activity. PKC activity was measured after semipurification with nondenaturing polyacrylamide gel electrophoresis in the cytosol and the particulate fraction of A549 cells. When cells were exposed to TPA or mezerein, PKC activity underwent rapid and concentration-dependent translocation from the cytosol to the membrane. TPA at 0.1 µM or mezerein at 1 µM caused almost complete translocation within 30 min. Incubation with bryostatins 1 or 2 also led to enzyme translocation, which was, however, much weaker than that observed with the tumor promoters. Neither 4-phorboldidecanoate nor the synthetic diacylglycerols 1,2-sn-dioctanoylglycerol or 1-oleoyl-2-acetyl-sn-glycerol mimicked TPA in this way. Exposure of cells to TPA or the bryostatins for longer than 30 min caused the gradual disappearance of total cellular PKC activity. PKC downregulation was concentration dependent and complete after 24 h. A549 cells which had acquired temporary resistance toward the growth-arresting potential of TPA were completely devoid of any measurable PKC activity. The bryostatins were potent inhibitors of the binding of [³H]phorbol-12,13-dibutyrate to its receptors in intact cells, and the inhibition was dependent on bryostatin concentration. The results support the contention that PKC is involved in the mediation of growth inhibition caused by TPA or the bryostatins. However, the relationship between growth arrest and PKC translocation or downregulation seems to be a complex one.

¹ Supported by Grant SP 1518 from the Cancer Research Campaign of Great Britain. The isolation of the bryostatins was funded by NIH Grant CA 16049, the Fannie E. Rippel Foundation, the Arizona Disease Control Research Commission, and the Robert B. Dalton Endowment Fund.

² To whom requests for reprints should be addressed.

Received 12/ 5/88. Revised 3/ 6/89. Accepted 3/14/89.

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