Glucocorticoid protects hepatoma cells against metabolic stress-induced cell death

Abstract

Hepatocellular carcinoma is one of the most common cancers in the world. Previously, we found that the level of glucocorticoid receptor was significantly higher in hepatocellular carcinoma than in adjacent liver tissues. Moreover, in vitro and in vivo studies showed that glucocorticoid stimulated the growth of hepatoma cells. On the other hand, endogenous metabolites such as 2-methoxyestradiol, a metabolite of estrogen produced in liver, and lactic acid, an end-product of glycolysis can result in apoptosis of tumor cells. There are studies that glucocorticoid inhibited apoptosis induced by different chemotherapeutic drugs, whether glucocorticoid could block endogenous stresses, such as 2-methoxyestradiol- or lactic acid-induced apoptosis in human and murine hepatoma cells is not known. In this study, the antagonistic effects of dexamethasone on 2-methoxyestradiol- and lactic acid-induced apoptosis were investigated in human HepG2 and murine Hepa1-6 hepatoma cells. Treatment of hepatoma cells with 2.5-10 microM 2-methoxyestradiol or 25 mM lactic acid resulted in growth inhibition and decreased viability. In addition, results of cell cycle analysis, annexin V binding assay and DNA fragmentation formation showed that 2-methoxyestradiol- or lactic acid-induced apoptosis of hepatoma cells but these effects were partially blocked by dexamethasone. Combined treatment of hepatoma cells with dexamethasone and 2-methoxyestradiol or lactic acid partially reduced the 2-methoxyestradiol- or lactic acid-induced apoptosis signal. Treatment of hepatoma cells with 2-methoxyestradiol or lactic acid resulted in up-regulation of caspase-8, -9 and -3. Dexamethasone partially suppressed the caspase expression. The Bcl-2 level was induced by dexamethasone treatment but decreased after treatment with 2-methoxyestradiol or lactic acid. These results together suggest that glucocorticoids may protect hepatoma cells from metabolic stress-induced cell damage via anti-apoptotic pathways.