Autophagy activated by silibinin contributes to glioma cell death via induction of oxidative stress-mediated BNIP3-dependent nuclear translocation of AIF
Autophagy activated by silibinin contributes to glioma cell death via induction of oxidative stress-mediated BNIP3-dependent nuclear translocation of AIF
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水飞蓟宾激活的自噬通过诱导氧化应激介导的 BNIP3 依赖性 AIF 核易位导致神经胶质瘤细胞死亡
DOI：
10.1038/s41419-020-02866-3
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发表时间：
2020-08-14
影响因子：
9
通讯作者：
Ge, Pengfei
中科院分区：
文献类型：
--
作者：
Wang, Chongcheng;He, Chuan;Ge, Pengfei
诱导致死性自噬已成为消除胶质瘤细胞的一种策略，但自噬是否通过导致线粒体损伤和凋亡诱导因子(AIF)的核转位而导致细胞死亡仍不清楚。在本研究中，我们发现水飞蓟宾在体内外诱导胶质瘤细胞AIF从线粒体到细胞核的移位，并伴随着自噬激活。体外研究表明，用3MA、巴菲洛霉素A1阻断自噬或用siRNA敲除ATG5可抑制水飞蓟宾诱导的线粒体超氧化物积聚、AIF从线粒体到细胞核的移位以及胶质瘤细胞的死亡。从机制上讲，水飞蓟宾通过抑制糖酵解消耗三磷酸腺苷来激活自噬。然后，自噬通过促进P53介导的谷胱甘肽和半胱氨酸的消耗和XCT的下调来改善细胞内的过氧化氢。增加的过氧化氢促进水飞蓟宾诱导的BNIP3上调和移位到线粒体。用siRNA敲除BNIP3可以抑制水飞蓟宾诱导的线粒体去极化、线粒体超氧化物的积累和AIF从线粒体到细胞核的移位，并防止胶质瘤细胞的死亡。此外，我们发现改进的过氧化氢加强了水飞蓟宾诱导的糖酵解功能障碍。总之，自噬通过促进氧化应激介导的BNIP3依赖的AIF核转位，促进水飞蓟宾诱导的胶质瘤细胞死亡。
Induction of lethal autophagy has become a strategy to eliminate glioma cells, but it remains elusive whether autophagy contributes to cell death via causing mitochondria damage and nuclear translocation of apoptosis inducing factor (AIF). In this study, we find that silibinin induces AIF translocation from mitochondria to nuclei in glioma cells in vitro and in vivo, which is accompanied with autophagy activation. In vitro studies reveal that blocking autophagy with 3MA, bafilomycin A1 or by knocking down ATG5 with SiRNA inhibits silibinin-induced mitochondrial accumulation of superoxide, AIF translocation from mitochondria to nuclei and glioma cell death. Mechanistically, silibinin activates autophagy through depleting ATP by suppressing glycolysis. Then, autophagy improves intracellular H2O2 via promoting p53-mediated depletion of GSH and cysteine and downregulation of xCT. The increased H2O2 promotes silibinin-induced BNIP3 upregulation and translocation to mitochondria. Knockdown of BNIP3 with SiRNA inhibits silibinin-induced mitochondrial depolarization, accumulation of mitochondrial superoxide, and AIF translocation from mitochondria to nuclei, as well as prevents glioma cell death. Furthermore, we find that the improved H2O2 reinforces silibinin-induced glycolysis dysfunction. Collectively, autophagy contributes to silibinin-induced glioma cell death via promotion of oxidative stress-mediated BNIP3-dependent nuclear translocation of AIF.