6-dehydrogingerdione sensitizes human hepatoblastoma Hep G2 cells to TRAIL-induced apoptosis via reactive oxygen species-mediated increase of DR5

The Anticancer effects of 6-dehydrogingerdione (6-DG), a compound isolated from the rhizomes of Zingiber officinale , and its mechanisms of sensitization to TRAIL-induced Apoptosis were studied using human hepatoblastoma Hep G2 cells. This study demonstrates for the first time that 6-DG-induced Apoptosis might be executed via mitochondrial- and Fas receptor-mediated pathways. Further studies also demonstrated that 6-DG could sensitize Hep G2 cells to TRAIL-induced Apoptosis. 6-DG also up-regulated Ser-15 phosphorylation and evoked p53 nuclear translocation. Abrogation of p53 expression by p53 small interfering RNA significantly attenuated 6-DG-induced DR5 expression, thus rendering these cells resistant to TRAIL-induced Apoptosis. DR5 expression after 6-DG treatment was accompanied by provoking intracellular Reactive Oxygen Species (ROS) generation. Pretreatment with N-acetyl-l-cysteine (NAC) attenuated 6-DG-induced DR5 expression and inhibited TRAIL-induced Apoptosis. In contrast to Hep G2 cells, DR5 up-regulation and sensitization to TRAIL-induced Apoptosis instigated by 6-DG were not observed in normal MDCK cells. Taken together, these data suggested that in addition to the mitochondrial- and Fas receptor-mediated apoptotic pathways involved, ROS-dependent and p53-regulated DR5 expression was also demonstrated to play a pivotal role in the synergistic enhancement of TRAIL-induced Apoptosis instigated by 6-DG in Hep G2 cells.