Activity of phorbol ester tumor promoters on enucleated Swiss 3T3 cells

The site of action of the phorbol esters, potent tumor promoters, is not known. To evaluate the possible role of the nucleus in the specific interaction of phorbol esters with cells, the activity of phorbol-12-myristate-13-acetate was determined on intact and enucleated Swiss 3T3 mouse cells. The parameter which was used as a measure of cellular response was the morphological change of transient cell rounding and process formation which was induced in these cells within 2 hr by biologically active phorbol esters. We found no effect of the cell nucleus on the responsiveness of the cells to phorbol-12-myristate-13-acetate. Likewise, the responsiveness of the cells to phorbol-12,13-dibenzoate, phorbol-12,13-diacetate, and phorbol-13-acetate was nuclear independent. These three derivatives were examined because they have comparable efficacies to phorbol-12-myristate-13-acetate (i.e., similar maximal effects) in a variety of in vitro systems but vary greatly (10,000-fold) in potency. We conclude that the phorbol ester receptor coupled to the morphological response (and presumably those other cellular responses which share the same structure-activity requirements) is nonnuclear.