RIP1 and RIP3 contribute to shikonin-induced glycolysis suppression in glioma cells via increase of intracellular hydrogen peroxide
RIP1 and RIP3 contribute to shikonin-induced glycolysis suppression in glioma cells via increase of intracellular hydrogen peroxide
复制标题
RIP1 和 RIP3 通过增加细胞内过氧化氢来抑制紫草素诱导的神经胶质瘤细胞糖酵解
DOI：
10.1016/j.canlet.2018.03.046
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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：
Lu, Bin;Wang, Zongqi;Ge, Pengfei
RIP 1和RIP 3是坏死性凋亡的启动因子，但其在糖酵解调控中的作用尚不清楚。本研究发现紫草素在体外和体内均可激活胶质瘤细胞中的RIP 1和RIP 3，并伴有糖酵解抑制。进一步的研究表明，当RIP 1或RIP 3被siRNA抑制或基因敲低时，紫草素诱导的葡萄糖-6-磷酸和丙酮酸的减少以及HK II和PKM 2的下调被显著阻止。此外，紫草素还引发细胞内H2 O2的积累和GSH和半胱氨酸的消耗。通过补充GSH减轻细胞内H2 O2逆转紫草素诱导的糖酵解抑制。在外源性H2 O2处理的细胞中，进一步证实了细胞内H2 O2在调节糖酵解抑制中的作用。值得注意的是，RIP 1或RIP 3的抑制防止细胞内H2 O2的积累，这与防止紫草素诱导的x-CT下调和GSH和半胱氨酸的消耗有关。此外，丙酮酸的补充有效地抑制紫草素或外源性H2 O2诱导的细胞内H2 O2的积累和胶质瘤细胞的死亡。综上所述，我们在这项研究中证明，RIP 1和RIP 3通过增加细胞内H2 O2来促进紫草素诱导的糖酵解抑制。(C)2018爱思唯尔B. V.保留所有权利。
RIP1 and RIP3 are necroptosis initiators, but their roles in regulation of glycolysis remain elusive, In this study, we found shikonin activated RIP1 and RIP3 in glioma cells in vitro and in vivo, which was accompanied with glycolysis suppression. Further investigation revealed that shikonin-induced decreases of glucose-6-phosphate and pyruvate and downregulation of HK II and PKM2 were significantly prevented when RIP1 or RIP3 was pharmacologically inhibited or genetically knocked down with SiRNA. Moreover, shikonin also triggered accumulation of intracellular H2O2 and depletion of GSH and cysteine. Mitigation of intracellular H2O2 via supplement of GSH reversed shikonin-induced glycolysis suppression. The role of intracellular H2O2 in regulation of glycolysis suppression was further confirmed in the cells treated with exogenous H2O2. Notably, inhibition of RIP1 or RIP3 prevented intracellular H2O2 accumulation, which was correlated with preventing shikonin-induced downregulation of x-CT and depletion of GSH and cysteine. In addition, supplement of pyruvate effectively inhibited shikonin- or exogenous H2O2-induced accumulation of intracellular H2O2 and glioma cell death. Taken together, we demonstrated in this study that RIP1 and RIP3 contributed to shikonin-induced glycolysis suppression via increasing intracellular H2O2. (C) 2018 Elsevier B.V. All rights reserved.