BNIP3 contributes to silibinin-induced DNA double strand breaks in glioma cells via inhibition of mTOR.
BNIP3 contributes to silibinin-induced DNA double strand breaks in glioma cells via inhibition of mTOR.
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DOI：
10.1016/j.bbrc.2021.11.110
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发表时间：
2021-12
影响因子：
3.1
通讯作者：
C. Hua;Xuanzhong Wang;Shipeng Liang;Xi Chen;Chen Li;Guangqiang You;Chong-cheng Wang;Tian-fei Luo;Zhen-chuan Wang;Pengfei Ge-
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文献类型：
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作者：
C. Hua;Xuanzhong Wang;Shipeng Liang;Xi Chen;Chen Li;Guangqiang You;Chong-cheng Wang;Tian-fei Luo;Zhen-chuan Wang;Pengfei Ge-
BNIP3可以通过引起线粒体损伤和内质网应激来消除癌细胞，但其在调节DNA双链断裂（DSB）中的作用尚不清楚。在本研究中，我们发现水飞蓟宾在胶质瘤细胞中触发DNA双链断裂，ROS积累和BNIP3表达上调。用抗氧化剂GSH减轻ROS显著抑制水飞蓟宾诱导的DNA DSB和胶质瘤细胞死亡。然后，我们发现用SiRNA敲低BNIP3明显地阻止了水飞蓟宾诱导的DNA双链断裂和ROS积累。从机制上讲，BNIP3敲低不仅通过维持xCT水平逆转水飞蓟宾触发的半胱氨酸和GSH消耗，而且消除过氧化氢酶减少。值得注意的是，当BNIP3被敲低时，水飞蓟宾诱导的mTOR去磷酸化也被阻止。鉴于活化的mTOR可以促进xCT表达并抑制过氧化氢酶的自噬降解，我们的数据表明BNIP3通过抑制mTOR改善细胞内ROS而有助于水飞蓟宾诱导的DNA DSB。
BNIP3 is found to eliminate cancer cells via causing mitochondrial damage and endoplasmic reticulum stress, but it remains elusive of its role in regulating DNA double strand breaks (DSBs). In this study, we find that silibinin triggers DNA DSBs, ROS accumulation and expressional upregulation of BNIP3 in glioma cells. Mitigation of ROS with antioxidant GSH significantly inhibits silibinin-induced DNA DSBs and glioma cell death. Then, we find knockdown of BNIP3 with SiRNA obviously prevents silibinin-induced DNA DSBs and ROS accumulation. Mechanistically, BNIP3 knockdown not only reverses silibinin-triggered depletion of cysteine and GSH via maintaining xCT level, but also abrogates catalase decrease. Notably, silibinin-induced dephosphorylation of mTOR is also prevented when BNIP3 is knocked down. Given that activated mTOR could promote xCT expression and inhibit autophagic degradation of catalase, our data suggest that BNIP3 contributes to silibinin-induced DNA DSBs via improving intracellular ROS by inhibition of mTOR.