2. Academic Validation
  3. 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

  • Cell Death Dis. 2020 Aug 14;11(8):630. doi: 10.1038/s41419-020-02866-3.
Chongcheng Wang 1 2,  Chuan He 1 2,  Shan Lu 1 2,  Xuanzhong Wang 1 2,  Lei Wang 1 2,  Shipeng Liang 1 2,  Xinyu Wang 3,  Meihua Piao 4,  Jiayue Cui 5,  Guangfan Chi 6,  Pengfei Ge 7 8
Affiliations

Affiliations

  • 1 Department of Neurosurgery, First Hospital of Jilin University, 130021, Changchun, China.
  • 2 Research Center of Neuroscience, First Hospital of Jilin University, 130021, Changchun, China.
  • 3 Department of Radiotherapy, Second Hospital of Jilin University, 130021, Changchun, China.
  • 4 Department of Anesthesiology, First Hospital of Jilin University, 130021, Changchun, China.
  • 5 Department of Histology and Embryology, College of Basic Medical Sciences, Jilin University, 130021, Changchun, China.
  • 6 Key Laboratory of Pathobiology, Ministry of Education, Jilin University, 130021, Changchun, China.
  • 7 Department of Neurosurgery, First Hospital of Jilin University, 130021, Changchun, China. gepf@jlu.edu.cn.
  • 8 Research Center of Neuroscience, First Hospital of Jilin University, 130021, Changchun, China. gepf@jlu.edu.cn.
PMID: 32801360 DOI: 10.1038/s41419-020-02866-3
Abstract

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.

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