Garcinol potentiates TRAIL-induced apoptosis through modulation of death receptors and antiapoptotic proteins.
Garcinol potentiates TRAIL-induced apoptosis through modulation of death receptors and antiapoptotic proteins.
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DOI：
10.1158/1535-7163.mct-09-1113
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发表时间：
2010-04
影响因子：
5.7
通讯作者：
Aggarwal BB
中科院分区：
文献类型：
--
作者：
Prasad S;Ravindran J;Sung B;Pandey MK;Aggarwal BB
研究了Garcinia indica的活性成分Garcinol是否可以调节癌细胞对TRAIL的敏感性，TRAIL是目前处于II期临床试验的细胞因子。我们发现加苯二酚增强TRAIL诱导的癌细胞凋亡，如细胞内酯酶活性、DNA链断裂、膜磷脂磷脂酰丝氨酸的积累、线粒体活性和半胱天冬酶-8、-9和-3的活化所示。我们发现，Garcinol，独立于细胞类型，诱导TRAIL受体，死亡受体（DR）-4和DR 5。Garcinol既不诱导正常细胞上的受体，也不使它们对TRAIL敏感。用小干扰RNA（siRNA）敲除DR 5或DR 4可显著降低TRAIL和Garcinol诱导的细胞凋亡。此外，Garcinol下调各种细胞存活蛋白，包括Survivin，bcl-2，XIAP和cFLIP;并诱导bid切割，bax和细胞色素c释放。Garcinol诱导DR被认为是独立的CHOP，p53，bax，ERK或JNK的调制。Garcinol的影响是通过产生活性氧介导的，尽可能多的诱导DR，抗凋亡和促凋亡蛋白的调制和增强TRAIL诱导的细胞凋亡被N-乙酰半胱氨酸和谷胱甘肽废除。有趣的是，Garcinol也将TRAIL抗性细胞转化为TRAIL敏感细胞。总的来说，我们的结果表明，garcinol可以通过上调死亡受体和下调抗凋亡蛋白来增强TRAIL诱导的细胞凋亡。
Whether garcinol, the active component from Garcinia indica, can modulate the sensitivity of cancer cells to TRAIL, a cytokine currently in phase II clinical trial, was investigated. We found that garcinol potentiated TRAIL-induced apoptosis of cancer cells as indicated by intracellular esterase activity, DNA strand breaks, accumulation of the membrane phospholipid phosphatidylserine, mitochondrial activity, and activation of caspase-8, -9, and -3. We found that garcinol, independent of the cell type, induced both of the TRAIL receptors, death receptors (DR)-4 and DR5. Garcinol neither induced the receptors on normal cells, nor sensitized them to TRAIL. Deletion of DR5 or DR4 by small interfering RNA significantly reduced the apoptosis induced by TRAIL and garcinol. In addition, garcinol downregulated various cell survival proteins including survivin, bcl-2, XIAP and cFLIP; and induced bid cleavage, bax and cytochrome c release. Induction of DRs by garcinol was found to be independent of modulation of CHOP, p53, bax, ERK or JNK. The effect of garcinol was mediated through the generation of reactive oxygen species, in as much as both induction of DRs, modulation of antiapoptotic and proapoptotic proteins and potentiation of TRAIL-induced apoptosis were abolished by N-acetyl cysteine and glutathione. Interestingly, garcinol also converted TRAIL-resistant cells to TRAIL-sensitive. Overall, our results indicate that garcinol can potentiate TRAIL-induced apoptosis through upregulation of death receptors and downregulation of antiapoptotic proteins.