SYNERGISTIC STIMULATION OF PROSTAGLANDIN-E2 RELEASE BY EPIDERMAL GROWTH-FACTOR AND A TUMOR PROMOTER ANTHRALIN FROM PRIMARY CULTURES OF MOUSE EPIDERMAL-CELLS

The tumor promoter anthralin stimulated prostaglandin E2 (PGE2) and arachidonic acid release from primary cultures of mouse epidermal cells. Epidermal growth factor (EGF) hardly stimulated PGE2 release by itself; however, a combination of anthralin and EGF synergistically stimulated PGE2 release. Neither anthralin, EGF nor EGF plus anthralin affected the incorporation of arachidonic acid into cellular phospholipids at least up to 2 hr after the stimulation by these agents. In the presence of EGF, however, [H-3]arachidonic acid in the medium decreased substantially 4 -8 hr after the addition of this agent, indicating that EGF suppresses [H-3]arachidonic acid release and stimulates the incorporation of [H-3]arachidonic acid into the cells during this time period. Cellular cyclooxygenase activity was increased by treating the cells either with anthralin or EGF, and it was synergistically increased by EGF plus anthralin. Both cycloheximide and actinomycin D inhibited the increase in cyclooxygenase activity caused by EGF plus anthralin. These results indicate that the synergistic stimulation of PGE2 release caused by EGF plus anthralin is due to a synergistic stimulation of arachidonic acid release (in the early phase of stimulation) and a synergistic increase in cyclooxygenase activity, probably a synergistic induction of cyclooxygenase, by these agents.