Pseudolaric acid B triggers ferroptosis in glioma cells via activation of Nox4 and inhibition of xCT
Pseudolaric acid B triggers ferroptosis in glioma cells via activation of Nox4 and inhibition of xCT
复制标题
伪桂酸 B 通过激活 Nox4 和抑制 xCT 触发神经胶质瘤细胞中的铁死亡
DOI：
10.1016/j.canlet.2018.04.021
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发表时间：
2018-01-01
期刊：
影响因子：
9.7
通讯作者：
Ge, Pengfei
中科院分区：
文献类型：
--
作者：
Wang, Zongqi;Ding, Ye;Ge, Pengfei
铁凋亡是一种程序性细胞死亡的形式，由铁依赖性脂质过氧化决定，但其在胶质瘤细胞死亡中的作用尚不清楚。在本研究中，我们发现假水杨酸B （Pseudolaric acid B， PAB）在体外和体内抑制胶质瘤细胞的生存能力，并伴有细胞内亚铁、H2O2和脂质过氧化的异常升高，以及GSH和半胱氨酸的消耗。体外研究发现，铁螯合剂去铁胺可抑制PAB引起的脂质过氧化和细胞死亡，但补充柠檬酸铁铵会加重PAB引起的细胞死亡。用铁他汀-1或谷胱甘肽抑制脂质过氧化可挽救乙胺酸诱导的细胞死亡。形态学上，PAB处理的细胞膜完整，线粒体缩小，膜密度增加，细胞核大小正常，没有染色质凝聚。机制上，PAB通过上调转铁蛋白受体改善细胞内铁。铁的增加激活了Nox4，导致H2O2和脂质过氧化物的过量产生。此外，PAB通过p53介导的xCT途径减少细胞内GSH，进一步加剧H2O2和脂质过氧化物的积累。因此，PAB引发胶质瘤细胞的铁下垂，是治疗胶质瘤的潜在药物。(C) 2018 Elsevier B.V.版权所有
Ferroptosis is a form of programmed cell death decided by iron-dependent lipid peroxidation, but its role in glioma cell death remains unclear. In this study, we found Pseudolaric acid B (PAB) inhibited the viabilities of glioma cells in vitro and in vivo, which was accompanied by abnormal increases of intracellular ferrous iron, H2O2 and lipid peroxidation, as well as depletion of GSH and cysteine. In vitro studies revealed that the lipid peroxidation and the cell death caused by PAB were both inhibited by iron chelator deferoxamine, but exacerbated by supplement of ferric ammonium citrate. Inhibition of lipid peroxidation with ferrostatin-1 or GSH rescued PAB-induced cell death. Morphologically, the cells treated with PAB presented intact membrane, shrunken mitochondria with increased membrane density, and normal-sized nucleus without chromatin condensation. Mechanistically, PAB improved intracellular iron by upregulation of transferrin receptor. The increased iron activated Nox4, which resulted in overproduction of H2O2 and lipid peroxides. Moreover, PAB depleted intracellular GSH via p53-mediated xCT pathway, which further exacerbated accumulation of H2O2 and lipid peroxides. Thus, PAB triggers ferroptosis in glioma cells and is a potential medicine for glioma treatment. (C) 2018 Elsevier B.V. All rights reserved.