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A Proposed Common Mechanism by Which Phorbol Esters and Epidermal Growth Factor Delay the Progression from G₂ Phase to Mitosis of HeLa Cells through Phospholipid Metabolites¹

Institute of Experimental Pathology [M. K., J. R., L. S., V. K.] and Institute of Biochemistry [G. F.], German Cancer Research Center, Im Neuenheimer Feld 280, D-6900 Heidelberg, Federal Republic of Germany

The phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA; also called phorbol myristate acetate) and epidermal growth factor both rapidly inhibit the transition of HeLa cells from G₂ phase to mitosis in a reversible fashion with characteristics of a receptor-mediated response. It was proposed that an intracellular mediator was responsible for this inhibition. In searching for a common mediator elicited by the action of both ligands, the time course of generation of phospholipid metabolites was compared with the cell cycle response of the G₂ cohort monitored by time lapse analysis. The time course and the degree of mobilization of diacylglycerols (DG) effected by TPA and by epidermal growth factor and that of phosphatidic acid correlated to a great extent with the onset and the duration of the G₂ inhibition caused by both agonists. Further evidence for the proposed role of DGs and/or phosphatidic acid was obtained by the observation that membrane-penetrating 1,2-DG inhibited HeLa cells in G₂ phase directly. The concentration of DG required correlated with that elicited by TPA or epidermal growth factor metabolically. This cellular response to 1,2-DG was also seen in cells after down-regulation of protein kinase C using TPA. The data indicate that cellular DG and/or phosphatidic acid may contribute to a restriction of cells in G₂ phase possibly by changing membrane properties.

¹ Work supported by the Deutsche Forschungsgemeinschaft.

² To whom requests for reprints should be addressed.

Received 10/15/90. Accepted 6/10/91.

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