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首页> 外文期刊>The Journal of Pharmacology and Experimental Therapeutics: Official Publication of the American Society for Pharmacology and Experimental Therapeutics >Silibinin induces cell death through reactive Oxygen species-dependent downregulation of Notch-1/ERK/Akt signaling in human breast cancer cells
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Silibinin induces cell death through reactive Oxygen species-dependent downregulation of Notch-1/ERK/Akt signaling in human breast cancer cells

机译：水飞蓟宾通过人类乳腺癌细胞中Notch-1 / ERK / Akt信号通路依赖活性氧的下调诱导细胞死亡

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摘要

The present study was undertaken to determine the underlying mechanism of silibinin-induced cell death in human breast cancer cell lines MCF7 and MDA-MB-231. Silibinin-induced cell death was attenuated by antioxidants, N-Acetylcysteine (NAC) and 6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid, suggesting that the effect of silibinin was dependent on generation of reactive oxygen species (ROS). Western blot analysis showed that silibinin induced downregulation of extracellular signal-regulated kinase (ERK) and Akt. When cells were transiently transfected with constitutively active (ca)mitogen-Activated protein kinase (MEK), an upstream kinase of ERK and caAkt, they showed resistance to silibinin-induced cell death. Silibinin decreased the cleavage of Notch-1 mRNA and protein levels. Notch- 1-overexpressed cells were resistant to the silibinin-induced cell death. Inhibition of Notch-1 signaling was dependent on ROS generation. Overexpression of Notch-1 prevented silibinin-induced inhibition of ERK and Akt phosphorylation. Silibinin-induced cell death was accompanied by increased cleavage of caspase-3 and was prevented by caspase-3 inhibitor in MDA-MB-231 cells but not in MCF7 cells. Silibinin induced translocation of apoptosisinducing factor (AIF), which was blocked by NAC, and transfection of caMEK and caAkt. Silibinin-induced cell death was prevented by silencing of AIF expression using small interfering AIF RNA in MCF7 cells but not in MDA-MB-231 cells. In conclusion, silibinin induces cell death through an AIF-dependent mechanism in MCF7 cells and a caspase-3-dependent mechanism in MDA-MB-231 cells, and ROS generation and Notch-1 signaling act upstream of the ERK and Akt pathway. These data suggest that silibinin may serve as a potential agent for induction of apoptosis in human breast cancer cells.
机译：进行本研究以确定水飞蓟宾诱导的人乳腺癌细胞系MCF7和MDA-MB-231中细胞死亡的潜在机制。抗氧化剂，N-乙酰半胱氨酸（NAC）和6-羟基-2,5,7,8-四甲基苯并-2-羧酸减轻了水飞蓟宾诱导的细胞死亡，表明水飞蓟宾的作用取决于活性氧的产生（ROS）。蛋白质印迹分析表明，水飞蓟宾诱导细胞外信号调节激酶（ERK）和Akt的下调。当用组成型活性（ca）促分裂原活化蛋白激酶（MEK），ERK和caAkt的上游激酶瞬时转染细胞时，它们显示出对水飞蓟宾诱导的细胞死亡的抵抗力。水飞蓟宾减少了Notch-1 mRNA和蛋白水平的切割。 Notch-1过表达的细胞对水飞蓟宾诱导的细胞死亡具有抗性。 Notch-1信号的抑制取决于ROS的产生。 Notch-1的过度表达阻止水飞蓟宾诱导的ERK和Akt磷酸化抑制。水飞蓟宾诱导的细胞死亡伴随着caspase-3裂解的增加，并被MDA-MB-231细胞中的caspase-3抑制剂阻止，但MCF7细胞中没有。水飞蓟宾诱导被NAC阻断的凋亡诱导因子（AIF）的转位，以及caMEK和caAkt的转染。通过在MCF7细胞中使用小的干扰性AIF RNA沉默AIF表达来防止水飞蓟宾诱导的细胞死亡，但在MDA-MB-231细胞中则不能。总之，水飞蓟宾通过MCF7细胞中AIF依赖性机制和MDA-MB-231细胞caspase-3依赖性机制诱导细胞死亡，并且ROS生成和Notch-1信号传导作用于ERK和Akt途径的上游。这些数据表明水飞蓟宾可能作为诱导人乳腺癌细胞凋亡的潜在药物。

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