Downregulation of wild-type beta-catenin expression by interleukin 6 in human hepatocarcinoma HepG2 cells: a possible role in the growth-regulatory effects of the cytokine?

We investigated the antitumour effects of interleukin 6 (IL-6) on hepatocarcinoma HepG2 cells, endowed with high levels of a mutated, non-degradable, beta-catenin. IL-6 produced minimal growth-inhibitory effects and no apoptosis or gross changes in cell adhesion. Interestingly, however, it caused a consistent decrease in the cytoplasmic levels of wild-type, but not of mutated, beta-catenin protein. There was no effect on E-cadherin or gamma-catenin and a reduction in alpha-catenin occurred only at high concentrations. IL-4, a non-related cytokine, did not modify the content of beta-catenin. IL-6 did not influence beta-catenin mRNA levels. LiCl, a potent inhibitor of Glycogen Synthase Kinase 3beta (GSK3beta) activity, abrogated the IL-6-induced inhibition of wild-type beta-catenin. This indicates that IL-6 can affect wild-type beta-catenin through a post-transcriptional mechanism, probably involving degradation of the protein. This effect might be related to the growth-regulatory activities of IL-6 in other situations, but can not counteract the oncogenic expression of mutated beta-catenin in HepG2 cells or possibly in other tumour cells with similar gene mutations.