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Retinol Inhibition of Ornithine Decarboxylase Induction and G₁ Progression in Chinese Hamster Ovary Cells¹

Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, Arizona 85724

Vitamin A inhibits ornithine decarboxylase (ODC) induction in G₁ phase of the cell cycle of synchronous cultures of Chinese hamster ovary (CHO) cells. The retinol-promoted inhibition of ODC was not the result of an effect on general protein synthesis, was effective only in G₁ prior to the time an increase in ODC activity had begun, did not involve disruption of the G₁-phase increase in cyclic adenosine 3':5'-monophosphate-dependent protein kinase activity, and required transcription-dependent events for reversal. The inhibition of ODC induction was associated with a block of cell cycle progression in G₁ phase. In the presence of the vitamin, there was no incorporation of [³H]thymidine, no induction of S-phase-dependent S-adenosyl-L-methionine decarboxylase, and no ultimate cell doubling. The inhibition of ODC and the inhibition of S-phase transition displayed a similar concentration dependence, with 60% inhibition occurring in the presence of 80 µM retinol, a similar dependence on cell locus in early G₁ phase for efficacy, and a similar reversal after removal of the vitamin, with the increase in ODC preceding the increase in S-phase transition in a parallel fashion. Arrest of the cells at the G₁ retinol-sensitive restriction point prior to ODC induction resulted in the inhibition of the G₁-phase-dependent increase in RNA synthesis.

Other naturally occurring retinoids also inhibit CHO cell growth (retinal > retinol > retinyl acetate > retinoic acid). Retinal, the most potent, displayed a paradoxical effect on CHO cells. At very low concentrations (1 to 5 µM), retinal stimulated CHO growth parameters; ODC activity was enhanced in a parallel fashion. At higher concentrations, retinal inhibited in a manner similar to that described for retinol.

¹ This work was supported by USPHS Research Grant CA-14783 from the National Cancer Institute.

² To whom requests for reprints should be addressed.

³ Recipient of Research Career Development Award CA-00072 from the National Cancer Institute.

Received 1/16/79. Accepted 9/11/79.