Time-course regulation of survival pathways by epicatechin on HepG2 cells

Polyphenols, such as epicatechin, have been reported to exhibit a wide range of biological activities. The objective of the present study was to investigate the time-dependent regulation by epicatechin of survival/proliferation pathways in HepG2 cells. Treatment of HepG2 cells with 10 micromol/L epicatechin did not result in any cell damage up to 18 h, as evaluated by the lactate dehydrogenase assay. Moreover, the enhanced cell death evoked by an oxidative stress induced with tert-butyl hydroperoxide was prevented in the cells pretreated 4 or 18 h with epicatechin. Epicatechin-induced survival was a rapid event that was accompanied by early and sustained activation of major survival signaling proteins, such as AKT/phosphatidylinositol 3-kinase and extracellular-regulated kinase (activated from 5 min to 18 h), as well as protein kinase C (PKC)-alpha (30 min to 18 h), in concert with unaltered c-jun N-amino terminal kinase levels and early inactivation of key death-related signals like PKC-delta (5 min to 18 h). Additionally, reactive oxygen species generation was transiently reduced when cells were treated with 10 micromol/L epicatechin (15-240 min). These data suggest that epicatechin induces cellular survival through a tight regulation of survival/proliferation pathways that requires the integration of different signals and persists over time, the ultimate effect on HepG2 cells being regulated by the balance among these signals.