Dissociation of tumor promoter-stimulated ornithine decarboxylase activity and DNA synthesis in mouse epidermis in vivo and in vitro by fluocinolone acetonide, a tumor-promotion inhibitor

U. Lichti, T. J. Slaga, T. Ben, E. Patterson, H. Hennings, S. H. Yuspa

Research output: Contribution to journalArticle

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Abstract

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 4.1.1.17) 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 languageEnglish (US)
Pages (from-to)3908-3912
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume74
Issue number9
DOIs
StatePublished - Dec 1 1977
Externally publishedYes

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