The Herbal Compound Cryptotanshinone Restores Sensitivity in Cancer Cells That Are Resistant to the Tumor Necrosis Factor-related Apoptosis-inducing Ligand*
The Herbal Compound Cryptotanshinone Restores Sensitivity in Cancer Cells That Are Resistant to the Tumor Necrosis Factor-related Apoptosis-inducing Ligand*
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DOI：
10.1074/jbc.m113.483909
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发表时间：
2013-08
期刊：
影响因子：
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通讯作者：
A. Tse;Ka-Yu Chow;Hui Cao;Chi-Yan Cheng;H. Kwan;Hua Yu;Guo‐Yuan Zhu;Yiu-Cheong Wu;W. Fong-W.-Fon
中科院分区：
文献类型：
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作者：
A. Tse;Ka-Yu Chow;Hui Cao;Chi-Yan Cheng;H. Kwan;Hua Yu;Guo‐Yuan Zhu;Yiu-Cheong Wu;W. Fong-W.-Fon
背景：耐药性的发展是TRAIL抗癌治疗的主要问题。结果：隐丹参酮通过ROS信号诱导死亡受体5，从而增强trail诱导的细胞凋亡。结论：隐丹参酮可恢复TRAIL耐药癌细胞的TRAIL敏感性。意义：我们证明了天然化合物隐丹参酮的一种新的trail增强作用。肿瘤坏死因子相关凋亡诱导配体（Tumor necrosis factor-related apoptosis-inducing ligand， TRAIL）选择性诱导癌细胞凋亡，而非正常细胞。然而，由于TRAIL受体低水平表达导致的TRAIL耐药在癌细胞中广泛存在，阻碍了其在癌症治疗中的发展。因此，迫切需要能够使肿瘤细胞对trail介导的凋亡敏感的药物。我们研究丹参的主要生物活性成分丹参酮是否能上调TRAIL受体的表达。在主要的丹参酮中，隐丹参酮（cryptanshinone， CT）诱导TRAIL受体2 （DR5）表达的能力最好。我们进一步发现，CT能够促进trail诱导的A375黑色素瘤细胞死亡和凋亡。ct诱导的DR5诱导不具有细胞类型特异性，因为在其他类型的癌细胞中也观察到DR5诱导。DR5敲除消除了CT对TRAIL反应的增强作用。从机制上看，CT诱导DR5不依赖于p53，但依赖于CCAAT/增强子结合蛋白同源蛋白（CHOP）的诱导。CHOP的下调可消除ct诱导的DR5表达和trail介导的细胞死亡的相关增强。此外，ct诱导的ROS产生先于CHOP和DR5的上调以及随后细胞对TRAIL的敏感化。有趣的是，CT还将trail耐药的肺A549癌细胞转化为trail敏感细胞。综上所述，我们的研究结果表明，CT可以通过上调DR5来增强trail诱导的细胞凋亡。
Background: Development of resistance is major problem in TRAIL anti-cancer therapy. Results: Cryptotanshinone induces death receptor 5 via ROS signaling and therefore enhances TRAIL-induced apoptosis. Conclusion: Cryptotanshinone restores TRAIL sensitivity in TRAIL-resistant cancer cells. Significance: We demonstrate a novel TRAIL-enhancing action by natural compound cryptotanshinone. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis and kills cancer cells but not normal cells. However, TRAIL resistance due to low level of TRAIL receptor expression is widely found in cancer cells and hampers its development for cancer treatment. Thus, the agents that can sensitize the tumor cells to TRAIL-mediated apoptosis are urgently needed. We investigated whether tanshinones, the major bioactive compounds of Salvia miltiorrhiza (danshen), can up-regulate TRAIL receptor expression. Among the major tanshinones being tested, cryptotanshinone (CT) showed the best ability to induce TRAIL receptor 2 (DR5) expression. We further showed that CT was capable of promoting TRAIL-induced cell death and apoptosis in A375 melanoma cells. CT-induced DR5 induction was not cell type-specific, as DR5 induction was observed in other cancer cell types. DR5 knockdown abolished the enhancing effect of CT on TRAIL responses. Mechanistically, induction of the DR5 by CT was found to be p53-independent but dependent on the induction of CCAAT/enhancer-binding protein-homologous protein (CHOP). Knockdown of CHOP abolished CT-induced DR5 expression and the associated potentiation of TRAIL-mediated cell death. In addition, CT-induced ROS production preceded up-regulation of CHOP and DR5 and consequent sensitization of cells to TRAIL. Interestingly, CT also converted TRAIL-resistant lung A549 cancer cells into TRAIL-sensitive cells. Taken together, our results indicate that CT can potentiate TRAIL-induced apoptosis through up-regulation of DR5.