Growth inhibition of human hepatoma cells by acyclic retinoid is associated with induction of p21(CIP1) and inhibition of expression of cyclin D1

Acyclic retinoid (ACR), a novel synthetic retinoid, can prevent the recurrence of 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...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2002-07, Vol.62 (14), p.3997-4006
Main Authors: Suzui, Masumi, Masuda, Muneyuki, Lim, Jin T E, Albanese, Chris, Pestell, Richard G, Weinstein, I Bernard
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
beta Catenin
Carcinoma, Hepatocellular - drug therapy
Carcinoma, Hepatocellular - metabolism
Carcinoma, Hepatocellular - pathology
Cell Division - drug effects
Cell Division - physiology
Cyclin D1 - antagonists & inhibitors
Cyclin D1 - biosynthesis
Cyclin D1 - genetics
Cyclin-Dependent Kinase Inhibitor p21
Cyclins - biosynthesis
Cytoskeletal Proteins - antagonists & inhibitors
Cytoskeletal Proteins - physiology
G1 Phase - drug effects
Growth Inhibitors - pharmacology
Humans
Liver Neoplasms - drug therapy
Liver Neoplasms - metabolism
Liver Neoplasms - pathology
Phosphorylation - drug effects
Promoter Regions, Genetic
Retinoblastoma Protein - metabolism
RNA, Messenger - genetics
RNA, Messenger - metabolism
Trans-Activators
Tretinoin - analogs & derivatives
Tretinoin - pharmacology
Tumor Cells, Cultured
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Summary:Acyclic retinoid (ACR), a novel synthetic retinoid, can prevent the recurrence of 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 G(0)-G(1), 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 3beta, or beta-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 beta-catenin/T-cell factor pathway. Nevertheless, even in the presence of excess beta-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 beta-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.
ISSN:0008-5472
1538-7445