Different sensitivities of p42 mitogen-activated protein kinase to phorbol ester and okadaic acid tumor promoters among cell types.

The operational equivalence of different types of tumor promoters was studied by comparing immediate, early, and late effects of okadaic acid (OA) and 12-O-tetradecanoylphorbol-13-acetate (TPA) on the phosphorylation state of p42 mitogen-activated protein kinase isoform (ERK2) in eight different cell lines. In normal human and mouse fibroblasts, both agents stimulated immediate/early (15-60 min) phosphorylation of ERK2. In mouse 3T3 cells, enhanced phosphorylation of ERK2 was detected only within the first hour of treatment with TPA but not with OA. The early response to both TPA and OA, in turn, was lost in another established cell line, the PNT2 prostate epithelial cells, where we could detect increased levels of phosphorylated ERK2 only after a 24-hr treatment with OA. When the effect of OA was evaluated in different PNT cell strains, we observed that their capacity to respond to this agent, by stabilizing phosphorylated forms of ERK2, was lost in less differentiated strains. In HeLa S3 and HTC tumor cells, however, neither TPA nor OA treatment led to any detectable increase in ERK2 phosphorylation at any time point analyzed. We conclude that the effects of OA and TPA on the phosphorylation states of ERK2 could be related to the cell type, and that the operational equivalence between these two different tumor promoters is maximal in normal cells.