Comparison of effects of bryostatins 1 and 2 and 12-O-tetradecanoylphorbol-13-acetate on protein kinase C activity in A549 human lung carcinoma cells.

Abstract

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 semi-purification 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 microM or mezerein at 1 microM 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 alpha-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.

• Authors: I L Dale, T D Bradshaw, A Gescher, G R Pettit
• Journal: Cancer research (Cancer Res) Vol. 49 Issue 12 Pg. 3242-5 (Jun 15 1989) ISSN: 0008-5472 [Print] United States
• PMID: 2720677 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Bryostatins
• Lactones
• Macrolides
• bryostatin 1
• bryostatin 2
• Protein Kinase C
• Tetradecanoylphorbol Acetate

Topics

• Antineoplastic Agents (pharmacology)
• Bryostatins
• Cell Line
• Cytosol (enzymology)
• Humans
• Kinetics
• Lactones (pharmacology)
• Lung Neoplasms
• Macrolides
• Membranes (enzymology)
• Protein Kinase C (metabolism)
• Tetradecanoylphorbol Acetate (pharmacology)