Dysregulation of glycogen synthase kinase-3β signaling in hepatocellular carcinoma cells

Christèle Desbois-Mouthon, Marie José Blivet-Van Eggelpoël, Eléonore Beurel, Mathieu Boissan, Roland Delélo, Axelle Cadoret, Jacqueline Capeau

Research output: Contribution to journalArticlepeer-review

76 Scopus citations


It has been reported that upstream components of the insulin-like growth factor (IGF) signaling axis could be overexpressed during hepatocarcinogenesis in humans and rodents. However, the signal transduction pathways activated downstream have been poorly studied. Here, we examined whether glycogen synthase kinase-3β (GSK-3β) could be a target in human hepatoma cell lines and transgenic ASV mice with hepatic expression of the SV40 large T antigen. In HuH7, Mahlavu, and Hep3B cells, basal levels of GSK-3βSer9 phosphorylation were strongly elevated, indicating that GSK-3β was inhibited. GSK-3β phosphorylation was insensitive to exogenous IGFs and was blocked with an IGF-1 receptor-neutralizing antibody in Mahlavu and Hep3B cells. By using LY294002 and ML-9, which act as phosphatidylinositol 3-kinase (PI3-K) and Akt inhibitors, respecthvely, we showed that GSK-3β phosphorylation required PI3-K activation in both cell lines whereas downstream Akt activation was required only in Mahlavu cells. However, in the 2 cell lines, GSK-3βSer9 phosphorylation was controlled by protein kinase C (PKC)ζ because it was blocked by an inhibitory PKCζ peptide. The blockage of GSK-3β phosphorylation markedly inhibited glycogen synthesis and decreased β-catenin expression. In addition, the overexpression of a constitutively active GSK-3β reduced AP-1-mediated gene transcription in Hep3B cells. Finally, we observed that reexpression of IGF-2 in tumoral livers from ASV mice was associated with a marked phosphorylation of GSK-3β. In conclusion, our results identify GSK-3β as a molecular target of the constitutive activation of the IGF axis in in vitro and in vivo models of hepatocarcinogenesis. Persistent phosphorylation of GSK-3β could be critical for regulation of glycogen metabolism and cell growth in hepatoma cells.

Original languageEnglish (US)
Pages (from-to)1528-1536
Number of pages9
Issue number6
StatePublished - Dec 1 2002
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology


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