Suramin inhibits growth and yet promotes insulin-like growth factor II expression in HepG2 cells

Suramin, a drug shown to inhibit the growth of some tumor cell types in vivo and in vitro, was found to strongly inhibit the proliferation of the human hepatoma cell line, HepG2, grown in either serum-supplemented medium or a serum-free, hormonally defined medium tailored for hepatoma cells. In parallel, suramin induced the expression of the 6.0-kilobase transcript of insulin-like growth factor II (IGF II) but had no significant effect on transforming growth factor beta 1 mRNA levels in these cells. The induction in the abundance of IGF II mRNA was posttranscriptionally regulated. The growth-inhibitory effect of suramin was not mediated through IGF II, since addition of IGF II directly to the medium mildly stimulated the growth of HepG2 cells in a dose-responsive manner. Treatment of cells with suramin for 24 h resulted also in increased albumin mRNA levels in both HepG2 cells and normal rat hepatocytes. Suramin's effect on albumin occurred only in cells in medium supplemented with serum and in freshly plated cells, i.e., cells that had not been in culture long enough to form their own extracellular matrix substratum. We hypothesize that, as for heparin, suramin can bind serum factor(s), adversely affecting the stability of albumin mRNA. Addition of either IGF I or IGF II directly to cells resulted in an increase in albumin mRNA in HepG2 cells after 4 days in culture, implicating a role for these factors in differentiation. Yet they showed no effect unless the cells were grown for 2 days in serum-supplemented medium and then switched to a hormonally defined medium. Thus, both mitogenic and differentiation effects of IGFs were observed, and the qualitative responses of the cells to IGFs were dictated by other variables. Neither suramin nor IGF II had an effect on total sulfation levels in cells or medium conditioned by HepG2 cells and rat hepatocytes, suggesting that they have few, if any, effects on glycosaminoglycan synthesis or the extent of sulfation. Therefore, at present, suramin's potent biological effects on the growth and differentiation of HepG2 cells and rat hepatocytes are clearly complex and mediated through as yet unclear mechanisms.