Honokiol induces autophagic cell death in malignant glioma through reactive oxygen species-mediated regulation of the p53/PI3K/Akt/mTOR signaling pathway
Honokiol induces autophagic cell death in malignant glioma through reactive oxygen species-mediated regulation of the p53/PI3K/Akt/mTOR signaling pathway
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DOI：
10.1016/j.taap.2016.05.018
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发表时间：
2016-08-01
影响因子：
3.8
通讯作者：
Chen, Ruei-Ming
中科院分区：
文献类型：
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作者：
Lin, Chien-Ju;Chen, Ta-Liang;Chen, Ruei-Ming
厚朴酚是厚朴树皮中提取的一种有效成分，具有抗癌作用。细胞凋亡属于I型程序性细胞死亡，而自噬属于II型程序性细胞死亡。本研究证实，厚木酚可诱导U87 MG胶质瘤细胞的细胞周期阻滞和凋亡。随后在本研究中，我们评估了厚木酚对胶质瘤细胞自噬的影响，并探讨了其分子机制。给颅内胶质瘤小鼠注射厚木酚可增加裂解型半胱天蛋白酶3和轻链3 (LC3)-II的表达。U87 MG细胞暴露于本木酚也能诱导细胞自噬，并呈浓度依赖性和时间依赖性。加入自噬抑制剂3-甲基腺嘌呤和自噬诱导剂雷帕霉素的结果证实，檀香醇诱导的自噬有助于细胞死亡。在体内和体外实验中，檀香醇降低PI3K蛋白水平、磷酸化(p)-Akt蛋白水平和雷帕霉素靶蛋白（mTOR）水平。预处理p53抑制剂或转染p53小干扰（si）RNA通过逆转p-Akt和p-mTOR表达下调来抑制檀香醇诱导的自噬。此外，红木酚引起活性氧（ROS）的产生，而活性氧被抗氧化剂维生素C抑制。维生素C还能抑制红木酚诱导的细胞自噬和凋亡。同时，在服用维生素C后，厚朴醇引起的p-p53、p53、p-Akt和p-mTOR水平的改变被减弱。综上所述，我们的数据表明，厚朴酚通过调节p53/PI3K/Akt/mTOR信号通路诱导ros介导的自噬细胞死亡。(C) 2016 Elsevier Inc.版权所有。
Honokiol, an active constituent extracted from the bark of Magnolia officinalis, possesses anticancer effects. Apoptosis is classified as type I programmed cell death, while autophagy is type II programmed cell death. We previously proved that honokiol induces cell cycle arrest and apoptosis of U87 MG glioma cells. Subsequently in this study, we evaluated the effect of honokiol on autophagy of glioma cells and examined the molecular mechanisms. Administration of honokiol to mice with an intracranial glioma increased expressions of cleaved caspase 3 and light chain 3 (LC3)-II. Exposure of U87 MG cells to honokiol also induced autophagy in concentration- and time-dependent manners. Results from the addition of 3-methyladenine, an autophagy inhibitor, and rapamycin, an autophagy inducer confirmed that honokiol-induced autophagy contributed to cell death. Honokiol decreased protein levels of PI3K, phosphorylated (p)-Akt, and p-mammalian target of rapamycin (mTOR) in vitro and in vivo. Pretreatment with a p53 inhibitor or transfection with p53 small interfering (si)RNA suppressed honokiol-induced autophagy by reversing downregulation of p-Akt and p-mTOR expressions. In addition, honokiol caused generation of reactive oxygen species (ROS), which was suppressed by the antioxidant, vitamin C. Vitamin C also inhibited honokiol-induced autophagic and apoptotic cell death. Concurrently, honokiol-induced alterations in levels of p-p53, p53, p-Akt, and p-mTOR were attenuated following vitamin C administration. Taken together, our data indicated that honokiol induced ROS-mediated autophagic cell death through regulating the p53/PI3K/Akt/mTOR signaling pathway. (C) 2016 Elsevier Inc. All rights reserved.