ROS and CHOP are critical for dibenzylideneacetone to sensitize tumor cells to TRAIL through induction of death receptors and downregulation of cell survival proteins.
ROS and CHOP are critical for dibenzylideneacetone to sensitize tumor cells to TRAIL through induction of death receptors and downregulation of cell survival proteins.
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DOI：
10.1158/0008-5472.can-10-3121
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发表时间：
2011-01-15
期刊：
影响因子：
11.2
通讯作者：
Aggarwal BB
中科院分区：
文献类型：
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作者：
Prasad S;Yadav VR;Ravindran J;Aggarwal BB
由于TRAIL选择性地杀死肿瘤细胞，它正在癌症患者中进行测试。不幸的是，患者对细胞因子产生抗性，因此，迫切需要能够使细胞对TRAIL敏感的试剂。在本研究中，我们研究了二亚苄基丙酮（DBA）是否可以敏化肿瘤细胞的TRAIL和加强TRAIL诱导的凋亡。如通过膜磷脂磷脂酰丝氨酸的积累、DNA断裂、细胞内酯酶活性和半胱天冬酶-8、-9和-3的活化所示，我们得出结论，DBA增强了结肠癌细胞中TRAIL诱导的凋亡。DBA还将TRAIL抗性细胞转化为TRAIL敏感细胞。当研究其机制时，我们发现DBA降低了抗凋亡蛋白和诱饵受体-2的表达，并增加了促凋亡蛋白的表达。DBA还诱导死亡受体（DR）-5和DR 4。通过小干扰RNA（SiRNA）敲低DR 5和DR 4降低DBA对TRAIL诱导的细胞凋亡的增敏作用。此外，DBA还能增加CHOP蛋白的表达。通过siRNA敲低CHOP降低了DBA诱导的DR 5表达和凋亡的诱导。然而，DBA对受体的诱导是不依赖于p53的，因为p53的缺失对受体诱导没有影响。我们观察到DBA诱导的DR 5和DR 4的诱导是通过产生活性氧（ROS）介导的，因为N-乙酰半胱氨酸阻断了DBA对死亡受体的诱导和对细胞存活蛋白的抑制。总的来说，我们的研究结果表明，DBA通过ROS介导的CHOP激活下调细胞存活蛋白和上调死亡受体来增强TRAIL诱导的细胞凋亡。
Because TRAIL selectively kills tumor cells, it is being tested in cancer patients. Unfortunately, patients develop resistance to the cytokine, therefore, agents which can sensitize cells to TRAIL are urgently needed. In the present study, we investigated whether dibenzylideneacetone (DBA) can sensitize cancer cells to TRAIL and potentiates TRAIL-induced apoptosis. As indicated by accumulation of the membrane phospholipid phosphatidylserine, DNA breaks, intracellular esterase activity, and activation of caspase-8, -9, and -3, we concluded that DBA potentiated TRAIL-induced apoptosis in colon cancer cells. DBA also converted TRAIL resistant-cells to TRAIL-sensitive. When examined for the mechanism, we found that DBA decreased the expression of antiapoptotic proteins and decoy recptor-2 and increased proapoptotic proteins. DBA also induced both death receptor (DR)-5 and DR4. Knockdown of DR5 and DR4 by small interfering RNA (SiRNA) reduced the sensitizing effect of DBA on TRAIL-induced apoptosis. In addition, DBA increased the expression of CHOP proteins. Knockdown of CHOP by siRNA decreased the induction of DBA-induced DR5 expression and apoptosis. Induction of receptors by DBA, however, was p53-independent, as deletion of p53 had no effect on receptor induction. We observed that DBA-induced induction of DR5 and DR4 was mediated through generation of reactive oxygen species (ROS), as N-acetylcysteine blocked the induction of death receptors and suppression of cell survival proteins by DBA. Overall, our results demonstrate that DBA potentiates TRAIL-induced apoptosis through downregulation of cell survival proteins and upregulation of death receptors via ROS-mediated CHOP activation.