Differential effects of various skin tumor-promoting agents on prostaglandin E₂ release from primary cultures of mouse epidermal cells

Prostaglandin E₂ (PGE₂) release from primary cultures of mouse epidermal cells was markedly stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA), mezerein and 1-oleoyl-2-acetyl-glycerol but not by 4α-phorbol-12,13-didecanoate in low Ca²⁺ (50 μM). TPA-evoked PGE₂ release was inhibited by mepacrine, indomethacin and H-7 but not by HA1004. These findings suggest that TPA stimulates PGE₂ release through activation of protein kinase C, phospholipase A₂ and the cyclooxygenase pathway. Of the non-TPA type of tumor promoting agents, i.e. anthralin, chrysarobin, 7-bromomethylbenz[a]anthracene, benzoylperoxide, okadaic acid and palytoxin, only anthralin stimulated PGE₂ release. Anthralin-evoked PGE₂ release was not inhibited by H-7. In normal Ca²⁺ (1.8 mM) medium, PGE₂ release increased markedly compared to the release in low Ca²⁺ medium. In normal Ca²⁺ medium, PGE₂ release was stimulated by TPA, anthralin and okadaic acid but not by other tumor promoting agents. In mouse peritoneal macrophages, TPA, palytoxin and okadaic acid stimulated PGE₂ release, but other tumor-promoting agents failed to stimulate it. These results suggest that skin tumor promoting agents are not necessarily effective stimulators of prostaglandin production either in macrophages or in epidermal cells, the target cells of skin tumor promotion.