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.
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.
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DOI：
10.1158/0008-5472.can-09-1161
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发表时间：
2009-08-15
期刊：
影响因子：
11.2
通讯作者：
Aggarwal BB
中科院分区：
文献类型：
--
作者：
Yodkeeree S;Sung B;Limtrakul P;Aggarwal BB
查明传统药物的活性成分和作用机制是非常必要的。我们研究了zerumbone，一种来自热带生姜的倍半萜，是否可以增强TRAIL的抗癌作用。我们发现zerumbone增强TRAIL诱导的人HCT 116结肠癌细胞凋亡，这与TRAIL死亡受体（DR）-4和DR 5的上调相关。DR的诱导发生在转录水平，并且这种诱导不是细胞类型特异性的，因为其表达在前列腺癌、肾癌、乳腺癌和胰腺癌细胞系中也上调。通过siRNA缺失DR 5或DR 4可显著降低TRAIL和zerumbone诱导的细胞凋亡。除了上调DR外，zerumbone还显著下调cFLIP的表达，但不下调其他抗凋亡蛋白的表达。谷胱甘肽和N-乙酰半胱氨酸（NAC）废除了zerumbone的两个DR的诱导，这与TRAIL诱导的细胞凋亡减少，表明活性氧（ROS）的关键作用。抑制ERK 1/2和p38 MAPK而不抑制Jun N-末端激酶可消除zerumbone对DR诱导的作用。Zerumbone也诱导p53肿瘤抑制基因，但被发现是可选的DR诱导或增强TRAIL诱导的细胞凋亡。bax和p21，然而，所需的zerumbone刺激TRAIL诱导的凋亡。总之，我们的研究结果表明，zerumbone可以通过ROS介导的ERK 1/2和p38 MPAPK的激活，导致DR 4和DR 5诱导，从而增强TRAIL的抗癌作用，从而增强TRAIL诱导的细胞凋亡。
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.