Induction of Apoptosis by Curcumin in Murine Myelomonocytic Leukemia WEHI-3 Cells is Mediated via Endoplasmic Reticulum Stress and Mitochondria-Dependent Pathways
Induction of Apoptosis by Curcumin in Murine Myelomonocytic Leukemia WEHI-3 Cells is Mediated via Endoplasmic Reticulum Stress and Mitochondria-Dependent Pathways
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DOI：
10.1002/tox.20716
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发表时间：
2013-05-01
影响因子：
4.5
通讯作者：
Chung, Jing-Gung
中科院分区：
文献类型：
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作者：
Huang, An-Cheng;Chang, Chia-Ling;Chung, Jing-Gung
姜黄素源自食品调味香料姜黄 (Curcuma longa)，已被证明具有抗癌活性并诱导多种癌细胞系凋亡。在我们之前的研究中，姜黄素能够在体内抑制小鼠骨髓单核细胞白血病WEHI-3细胞。然而，目前还没有关于姜黄素诱导 WEHI-3 细胞凋亡的细胞毒性反应和机制的报道。因此，我们假设姜黄素影响 WEHI-3 细胞并通过凋亡信号通路触发细胞死亡。通过流式细胞术分析、彗星实验、共聚焦激光显微镜和蛋白质印迹研究姜黄素对WEHI-3细胞的影响。在这项研究中，我们发现姜黄素以剂量依赖性（5-20μM）的方式诱导WEHI-3细胞凋亡。有趣的是，姜黄素增强了抗凋亡蛋白 Bcl-2 的水平，这可能表明姜黄素诱导的细胞凋亡是通过基于 WEHI-3 细胞中 CIEBP 同源蛋白 (CHOP)、激活转录因子 6 (ATF-6)、肌醇需求酶 1 (IRE1) 和 caspase-12 增加的 ER 应激信号通路来完成的。此外，姜黄素增加了 WEHI-3 细胞中活性氧 (ROS) 的产生和胞质 Ca2+ 的释放，并诱导 DNA 损伤，但降低了线粒体膜电位 (Delta Psi(m)) 的水平。总之，姜黄素诱导的细胞凋亡是通过 ROS 影响、线粒体介导和 ER 应激依赖性途径发生的。姜黄素作为治疗白血病的潜在治疗剂的评估似乎是有必要的。 (C) 2011 年 Wiley 期刊公司。Environ Toxicol 28：255-266，2013 年。
Curcumin, derived from the food flavoring spice turmeric (Curcuma longa), has been shown to exhibit anticancer activities and induce apoptosis in many types of cancer cell lines. In our previous study, curcumin was able to inhibit murine myelomonocytic leukemia WEHI-3 cells in vivo. However, there is no report addressing the cytotoxic responses and the mechanisms underlying curcumin-induced apoptotic cell death in WEHI-3 cells. Therefore, we hypothesized that that curcumin affected WEHI-3 cells and triggered cell death through apoptotic signaling pathways. The effects of curcumin on WEHI-3 cells were investigated by using flow cytometric analysis, comet assay, confocal laser microscopy and Western blotting. In this study, we found that curcumin induced apoptosis in WEHI-3 cells in a dose-dependent (5-20 mu M) manner. Interestingly, curcumin enhanced the level of the antiapoptotic protein Bcl-2 which might show that curcumin-induced apoptosis is done through the ER stress signaling pathways based on the increase of CIEBP homologous protein (CHOP), activating transcription factor 6 (ATF-6), inositol-requiring enzyme 1 (IRE1), and caspase-12 in WEHI-3 cells. Moreover, curcumin increased the reactive oxygen species (ROS) production and cytosolic Ca2+ release, and induced DNA damage, but decreased the level of mitochondrial membrane potential (Delta Psi(m)) in WEHI-3 cells. In conclusion, curcumin-induced apoptosis occurs through the ROS-affected, mitochondria-mediated and ER stress-dependent pathways. The evaluation of curcumin as a potential therapeutic agent for treatment of leukemia seems warranted. (C) 2011 Wiley Periodicals, Inc. Environ Toxicol 28: 255-266, 2013.