Cell cycle position affects response of normal fibroblasts to phorbol esters

Tumor-promoting phorbol ester derivatives are known to stimulate as well as inhibit the cell cycle traverse of many kinds of cells, but it is not known whether or how these effects are related to tumor promotion. It is shown here that the potency of the phorbol diester PMA (phorbol myristate acetate) to cause a delay of cell division depends on the cell cycle position at the beginning of exposure to the PMA. Quiescent human fibroblasts were stimulated with epidermal growth factor, and PMA was added to the cultures at different times after stimulation. The later PMA was added, the stronger was the mitotic delay it caused. This means that cells which become exposed while they are in an early stage of the cycle are less effectively delayed and reach mitosis earlier than those for which exposure begins at a later stage of the cycle. The data indicate that PMA is actually able to reverse the order in which the cells of a normally growing population divide. In organized tissues this could disturb the intercellular communication which may be linked to the relative cell cycle positions of neighboring cells.