Differential retinoic acid inhibition of ornithine decarboxylase induction by 12-O-tetradecanoylphorbol-13-acetate and by germicidal ultraviolet light

Abstract

Several retinoids including retinoic acid effectively inhibit phorbol ester-mediated tumor promotion and ornithine decarboxylase (ODC) induction in mouse epidermis. To understand better the possible cellular site of action of retinoids, the inhibitory action of retinoic acid on the induction of ODC was compared for two distinctly different inducers, namely, 12-O-tetradecanoylphorbol-13-acetate (TPA) and germicidal ultraviolet light (UV), in primary mouse epidermal cell cultures. It was found that the induction of ODC by TPA is almost completely prevented by 0.1 to 1 microM retinoic acid while the induction by UV is only moderately inhibited. Maximum inhibition is achieved by treating cells continuously with retinoic acid from 4 hr after plating, although pretreatment or simultaneous treatment relative to either inducer is almost as effective. When added after the inducer, retinoic acid loses its effectiveness as an inhibitor more rapidly for TPA induction than for UV induction of ODC. The differential inhibition of enzyme induction cannot be accounted for by selective retinoid inhibition of DNA, RNA, or protein synthesis either alone or in concert with TPA or UV. Other agents known to modulate the induction of ODC by TPA (fluocinolone acetonide, tosyl-L-lysylchloromethane, and local anesthetics) do not act differentially on UV induction. These agents possibly act at transcription or translation, both of which are required for ODC induction by TPA or UV. The preferential inhibition by retinoic acid of ODC induction by TPA is interpreted to result from specific interference at a unique and early site of interaction of TPA with the cell.