Inhibition by Prostaglandin Synthesis Inhibitors of the Induction of Epidermal Ornithine Decarboxylase Activity, the Accumulation of Prostaglandins, and Tumor Promotion Caused by 12-O-Tetradecanoylphorbol-13-acetate¹

Application of 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse skin results in a large and rapid induction of epidermal ornithine decarboxylase (ODC; EC 4.1.1.17) activity, a phenotypic change proposed to be essential for skin tumor promotion. Induction of ODC activity by TPA was inhibited by prior treatment of skin with inhibitors of prostaglandin synthesis in the order, indomethacin > naproxen > flufenamic acid > acetylsalicylic acid. In contrast, dexamethasone, a steroidal anti-inflammatory drug, was ineffective at a 280-nmol dose.

The inhibitory effect of indomethacin on ODC induction was found to be specific. The 280-nmol dose of indomethacin that inhibited the induction of ODC activity by 80% did not inhibit the induction by TPA of S-adenosylmethionine decarboxylase and cyclic adenosine 3′:5′-monophosphate phosphodiesterase (EC 3.1.4.17) activities. Furthermore, indomethacin treatment affected neither normal epidermal protein nor DNA synthesis.

The inhibition by the prostaglandin synthesis inhibitors of the induction of ODC activity by TPA was completely overcome by concurrent application of about 25 to 100 nmol of prostaglandins E₁, E₂, D₂, or the 6,9-thio analog of prostaglandin I₂ with TPA. In contrast, prostaglandins F_1α and F_2α, 6-keto-prostaglandin F_1α, or arachidonic acid at doses of as much as 100 nmol were ineffective. Application of 17 nmol of TPA led to about a 3-fold increase in epidermal levels of prostaglandins E and F, and that increase was blocked by pretreatment with 280 nmol of indomethacin.

Application of 280 nmol of indomethacin before each TPA treatment significantly inhibited the formation of skin papillomas. Prostaglandin E₂ alone could neither induce epidermal ODC activity nor promote skin tumors in an initiation/promotion experiment. However, potentiation of TPA-induced ODC activity by prostaglandin E₂ was observed.

The findings that the application of indomethacin prior to TPA treatment inhibits the accumulation of prostaglandins, the induction of ODC activity, and the formation of skin papillomas suggest that (a) prostaglandins E₁, E₂, D₂, and I₂ may play a role in the induction of ODC activity by TPA and that (b) TPA-induced ODC activity may be an important component of the mechanism of skin tumor promotion.