6‐Gingerol Induces Apoptosis through Lysosomal‐Mitochondrial Axis in Human Hepatoma G2 Cells

6‐Gingerol, a major phenolic compound derived from ginger, has been known to possess anticarcinogenic activities. However, the mechanisms are not well understood. In our previous study, it was demonstrated that lysosome and mitochondria may be the primary targets for 6‐gingerol in HepG2 cells. Therefore, the aim was to evaluate lysosome‐mitochondria cross‐signaling in 6‐gingerol‐induced apoptosis. Apoptosis was detected by Hoechst 33342 and TUNEL assay after 24 h treatment, and the destabilization of lysosome and mitochondria were early upstream initiating events. This study showed that cathepsin D played a crucial role in the process of apoptosis. The release of cathepsin D to the cytosol appeared to be an early event that preceded the release of cytochrome c from mitochondria. Moreover, inhibition of cathepsin D activity resulted in suppressed release of cytochrome c. To further determine the involvement of oxidative stress in 6‐gingerol‐induced apoptosis, the intracellular generation of reactive oxygen species (ROS) and reduced glutathione (GSH) were examined. Taken together, these results suggest that cathepsin D may be a positive mediator of 6‐gingerol induced apoptosis in HepG2 cells, acting upstream of cytochrome c release, and the apoptosis may be associated with oxidative stress. Copyright © 2012 John Wiley & Sons, Ltd.