Downregulation of wild-type β-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 3 beta (GSK3 beta) 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-trascriptional mechanism, probably involving degradation of the protein. This effect might be related to the growth-regulatory activities of IL-G in other situations, but call not counteract the oncogenic expression of mutated beta -catenin in HepG2 cells or possibly in other tumour cells with similar gene mutations. (C) 2001 Elsevier Science Ltd. All rights reserved.