Azadirone, a Limonoid Tetranortriterpene, Induces Death Receptors and Sensitizes Human Cancer Cells to Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) through a p53 Protein-independent Mechanism EVIDENCE FOR THE ROLE OF THE ROS-ERK-CHOP-DEATH RECEPTOR PATHWAY
Azadirone, a Limonoid Tetranortriterpene, Induces Death Receptors and Sensitizes Human Cancer Cells to Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) through a p53 Protein-independent Mechanism EVIDENCE FOR THE ROLE OF THE ROS-ERK-CHOP-DEATH RECEPTOR PATHWAY
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DOI：
10.1074/jbc.m113.455188
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发表时间：
2013-11-08
影响因子：
4.8
通讯作者：
Aggarwal, Bharat B.
中科院分区：
文献类型：
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作者：
Gupta, Subash C.;Francis, Sajin K.;Aggarwal, Bharat B.
尽管肿瘤坏死因子相关凋亡诱导配体（TRAIL）在2期临床试验中显示出疗效，但肿瘤细胞对TRAIL产生耐药性是一个主要障碍。我们研究了一种柠檬苦素类四降三萜，阿扎二酮是否能使人肿瘤细胞对TRAIL敏感。结果表明，氮杂二酮使癌细胞对TRAIL敏感。柠檬苦素诱导死亡受体（DR）5和DR 4的表达，但不影响诱饵受体在癌细胞中的表达。DR的诱导是通过ERK的激活和通过上调转录因子CCAAT增强子结合蛋白同源蛋白（CHOP）介导的，因为这些信号分子的沉默消除了氮杂二酮的作用。这些作用是癌细胞特异性的。DR 5基因上的CHOP结合位点是氮杂二酮诱导DR 5所必需的。DR的上调是通过活性氧（ROS）的产生介导的，因为ROS清除剂降低了氮杂二酮对ERK激活、CHOP上调、DR诱导和TRAIL致敏的作用。这种柠檬苦素诱导的DR不依赖于p53，但对TRAIL的敏感性依赖于p53。柠檬苦素下调细胞存活蛋白的表达，上调促凋亡蛋白的表达。发现氮杂二酮与TRAIL的组合在低于IC 50的浓度下是加和的，而在较高浓度下，该组合是协同的。总之，这项研究表明，氮杂二酮可以通过ROS-ERK-CHOP介导的DR 5和DR 4信号的上调，细胞存活蛋白的下调和促凋亡蛋白的上调，使癌细胞对TRAIL敏感。
Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown efficacy in a phase 2 clinical trial, development of resistance to TRAIL by tumor cells is a major roadblock. We investigated whether azadirone, a limonoidal tetranortriterpene, can sensitize human tumor cells to TRAIL. Results indicate that azadirone sensitized cancer cells to TRAIL. The limonoid induced expression of death receptor (DR) 5 and DR4 but did not affect expression of decoy receptors in cancer cells. The induction of DRs was mediated through activation of ERK and through up-regulation of a transcription factor CCAAT enhancer-binding protein homologous protein (CHOP) as silencing of these signaling molecules abrogated the effect of azadirone. These effects of azadirone were cancer cell-specific. The CHOP binding site on the DR5 gene was required for induction of DR5 by azadirone. Up-regulation of DRs was mediated through the generation of reactive oxygen species (ROS) as ROS scavengers reduced the effect of azadirone on ERK activation, CHOP up-regulation, DR induction, and TRAIL sensitization. The induction of DRs by this limonoid was independent of p53, but sensitization to TRAIL was p53-dependent. The limonoid down-regulated the expression of cell survival proteins and up-regulated the proapoptotic proteins. The combination of azadirone with TRAIL was found to be additive at concentrations lower than IC50, whereas at higher concentrations, the combination was synergistic. Overall, this study indicates that azadirone can sensitize cancer cells to TRAIL through ROS-ERK-CHOP-mediated up-regulation of DR5 and DR4 signaling, down-regulation of cell survival proteins, and up-regulation of proapoptotic proteins.