Zerumbone Enhances TRAIL-Induced Apoptosis through the Induction of Death Receptors in Human Colon Cancer Cells: Evidence for an Essential Role of Reactive Oxygen Species

摘要

Identification of the active component and mechanisms of action of traditional medicines is highly desirable. We investigated whether zerumbone, a sesquiterpene from tropical ginger, can enhance the anticancer effects of TRAIL. We found that zerumbone potentiated TRAIL-induced apoptosis in human HCT116 colon cancer cells and that this was correlated with the up-regulation of TRAIL death receptor (DR)-4 and DR5. Induction of DRs occurred at the transcriptional level, and this induction was not cell type specific as its expression was also upregulated in prostate, kidney, breast, and pancreatic cancer cell lines. Deletion of DR5 or DR4 by siRNA significantly reduced the apoptosis induced by TRAIL and zerumbone. In addition to up-regulating DRs, zerumbone also significantly down-regulated the expression of cFLIP, but not that of other antiapoptotic proteins. The induction of both DRs by zerumbone was abolished by glutathione and N-acetylcysteine (NAC), and this correlated with decreased TRAIL-induced apoptosis, suggesting a critical role of reactive oxygen species (ROS). Inhibition of ERK1/2 and p38 MAPK but not of Jun N-terminal kinase abolished the effect of zerumbone on DR induction. Zerumbone also induced the p53 tumor suppressor gene but was found to be optional for DR induction or for enhancement of TRAIL-induced apoptosis. Both bax and p21, however, were required for zerumbone to stimulate TRAIL-induced apoptosis. Overall, our results demonstrate that zerumbone can potentiate TRAIL-induced apoptosis through the ROS-mediated activation of ERK1/2 and p38 MPAPK leading to DR4 and DR5 induction and resulting in enhancement of the anticancer effects of TRAIL.