Ouabain elicits human glioblastoma cells apoptosis by generating reactive oxygen species in ERK-p66SHC-dependent pathway
Ouabain elicits human glioblastoma cells apoptosis by generating reactive oxygen species in ERK-p66SHC-dependent pathway
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DOI：
10.1007/s11010-014-2208-y
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发表时间：
2015-01-01
影响因子：
4.3
通讯作者：
Zheng, Jin
中科院分区：
文献类型：
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作者：
Yan, Xiaofei;Liang, FenLi;Zheng, Jin
过量活性氧（ROS）的产生是哇巴因抗肿瘤作用的主要机制之一。不幸的是，它下面的信号通路不是很清楚。在本研究中，我们研究了参与哇巴因诱导的ROS产生和细胞凋亡的人U373 MG和U87 MG胶质瘤细胞的分子机制。哇巴因诱导胶质母细胞瘤细胞凋亡并增加ROS产生。三种活性氧清除剂清除活性氧后，可部分逆转哇巴因诱导的细胞凋亡，但不能完全逆转。哇巴因诱导的活性氧产生不受钙超载，减少烟酰胺腺嘌呤二核苷酸磷酸氧化，但p66 Shc磷酸化。哇巴因处理增加p66 Shc Ser 36磷酸化。通过siRNA敲低p66 Shc显著抑制了响应哇巴因的ROS生成。哇巴因通过Src/Ras/细胞外信号调节激酶信号通路诱导p66 Shc磷酸化我们的研究结果揭示了一种新的信号通路与p66 Shc，哇巴因诱导的ROS的产生，胶质母细胞瘤细胞凋亡。
Excessive reactive oxygen species (ROS) generation has been implicated as one of main agents in ouabain-induced anticancer effect. Unfortunately, the signaling pathways under it are not very clarified. In the present study, we investigated the molecular mechanism involved in ouabain-induced ROS generation and cell apoptosis on human U373MG and U87MG glioma cells. Ouabain-induced glioblastoma cells apoptosis and increased ROS generation. Clearance ROS by three different ROS scavenger partly, but not totally, reversed ouabain's effect on cell apoptosis. Ouabain-induced ROS generation was not regulated by calcium overload, reduced nicotinamide adenine dinucleotide phosphate oxidation, but by p66Shc phosphorylation. Ouabain treatment increased p66Shc Ser36 phosphorylation. Knockdown of p66Shc by siRNA significantly inhibited ROS generations in response to ouabain. Ouabain-induced p66Shc phosphorylation through Src/Ras/extracellular signal-regulated kinase signal pathway. Our results uncovered a novel signaling pathway with p66Shc, ouabain-induced ROS generation, and glioblastoma cell apoptosis.