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Growth Inhibition of Human Hepatoma Cells by Acyclic Retinoid Is Associated with Induction of p21^CIP1 and Inhibition of Expression of Cyclin D1¹

Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, New York 10032 [M. S., M. M., J. T. E. L., I. B. W.], and Departments of Medicine and Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461 [C. A., R. G. P.]

Acyclic retinoid (ACR), a novel synthetic retinoid, can prevent the recurrenceof human hepatoma after surgical resection of primary tumors, but the molecular mechanisms by which ACR exerts antitumor effects are not known. In this study, we found that ACR inhibited the growth of three human hepatoma cell lines. In HepG2 cells, this inhibition was associated with an arrest of the cell cycle in G₀-G₁, increased cellular levels of p21^CIP1, decreased levels of the hyperphosphorylated form of the retinoblastoma protein, and decreased levels of cyclin D1, but no significant changes were seen in the levels of the p16^INK4a, p27^KIP1, cyclin-dependent kinase 4, cyclin-dependent kinase 6, glycogen synthase kinase 3ß, or ß-catenin proteins. ACR also caused a decrease in the level of cyclin D1 mRNA. Cotreatment of HepG2 human hepatoma cells with the proteasome inhibitor N-acetyl-Leu-Leu-norleu-al did not prevent the ACR-induced decrease in cyclin D1 protein, in contrast to the protective effect of N-acetyl-Leu-Leu-norleu-al on the cyclin D1 protein in cells treated with all-trans-retinoic acid. In transient transfection reporter assays, ACR, but not all-trans-retinoic acid, inhibited transcription from the cyclin D1 promoter. As reported previously in colon carcinoma cells, we found that in hepatoma cells, cyclin D1 promoter activity is markedly stimulated by the ß-catenin/T-cell factor pathway. Nevertheless, even in the presence of excess ß-catenin, ACR markedly inhibited the transcriptional activity of the cyclin D1 promoter. This is the first systematic study of the inhibitory effects of ACR, or any other retinoid compound, on ß-catenin/T-cell factor-stimulated cyclin D1 promoter activity in human tumor cells. These novel effects of ACR provide further evidence that ACR may be a valuable agent in the chemoprevention and therapy of hepatoma and possibly other human malignancies.

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