12-O-Tetradecanoyl phorbol-13-acetate (TPA), a tumor promoter, stimulates DNA synthesis in mouse epidermal cells in vivo and in vitro. This response appears to be mediated through polyamine metabolism because ornithine decarboxylase (L-ornithine carboxyl-lyase, EC 18.104.22.168) activity is markedly increased shortly after promoter exposure and this induction varies in magnitude according to dose and promoter potency of a series of phorbol esters. In vitro, exogenous putrescine (0.01-10 mM) results in a dose-related increase and prolongation of promoter-stimulated DNA synthesis, a phenomenon noted in other systems of polyamine-mediated growth stimulation. The anti-inflammatory steroid fluocinolone acetonide (FA), an inhibitor of tumor promotion, prevents TPA stimulation of epidermal proliferation in vivo and in vitro. In vitro, FA most effectively prevents stimulation of DNA synthesis when applied prior to TPA, and its continued presence after TPA treatment is not required. Paradoxically, FA potentiates the increase in ornithine decarboxylase activity after TPA administration both in vivo and in vitro. Furthermore, the inhibition of TPA-stimulated DNA synthesis by FA in vitro can be reversed by exogenous putrescine. These results suggest that FA exerts its antipromotion effect by reducing the sensitivity of the cell to polyamines or by reducing intracellular polyamine levels.
|Original language||English (US)|
|Number of pages||5|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Dec 1 1977|
ASJC Scopus subject areas