The anticancer flavonoid chrysin induces the unfolded protein response in hepatoma cells

Chrysin is a natural and biologically active flavonoid with anticancer effects. However, little is known about the adaptive response of cancer cells to chrysin. Chrysin reportedly has proteasome inhibitor activity. Previous studies demonstrated that proteasome inhibitors might induce endoplasmic reticulum (ER) stress response. In this study, we aimed to determine the effects of chrysin on hepatoma cells and roles of the ER-resident protein GRP78 (glucose-regulated protein 78) in its action. Also, we investigated the effects of green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG), a natural GRP78 inhibitor, on the sensitivity of hepatoma cells to chrysin. Here, we report that chrysin inhibits hepatoma cells growth and induces apoptosis in a dose-dependent manner. Chrysin induces GRP78 overexpression, X-box binding protein-1 splicing and eukaryotic initiation factor 2α phosphorylation, hallmarks of the unfolded protein response. GRP78 knockdown potentiates chrysin-induced caspase-7 cleavage in hepatoma cells and enhances chrysin-induced apoptosis. EGCG overcomes chrysin-induced GRP78 expression. Combination of EGCG potentiates chrysin-induced caspase-7 and poly (ADP-ribose) polymerase (PARP) cleavage. Finally, EGCG sensitizes hepatoma cells to chrysin through caspase-mediated apoptosis. These data suggest that chrysin triggers the unfolded protein response. Abrogation of GRP78 induction may improve the anticancer effects of chrysin. Combination of EGCG and chrysin represents a new regimen for cancer chemoprevention and therapeutics.