GSK621 Targets Glioma Cells via Activating AMP-Activated Protein Kinase Signalings.
GSK621 Targets Glioma Cells via Activating AMP-Activated Protein Kinase Signalings.
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GSK621 通过激活 AMP 激活的蛋白激酶信号传导靶向神经胶质瘤细胞
DOI：
10.1371/journal.pone.0161017
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Pan SJ
中科院分区：
文献类型：
--
作者：
Jiang H;Liu W;Zhan SK;Pan YX;Bian LG;Sun B;Sun QF;Pan SJ
在这里，我们研究了一种新型 AMP 激活蛋白激酶 (AMPK) 激活剂 GSK621 的抗神经胶质瘤细胞活性。我们发现 GSK621 对人神经胶质瘤细胞（U87MG 和 U251MG 系）具有细胞毒性，可能是通过引发 caspase 依赖性细胞凋亡而实现的。 Caspase 抑制剂可减轻其细胞毒性。 GSK621 激活 AMPK 抑制哺乳动物雷帕霉素靶蛋白 (mTOR) 并下调胶质瘤细胞中的四跨膜蛋白 8 (Tspan8)。通过 shRNA 敲低 AMPKα 或引入显性失活 (T172A) AMPKα，AMPK 抑制几乎逆转了 GSK621 诱导的 AMPK 激活、mTOR 抑制和 Tspan8 降解。因此，GSK621 在神经胶质瘤细胞中的细胞毒性也因 AMPKα 敲低或突变而显着减弱。进一步的研究表明，相对较低浓度的 GSK621 显着增强替莫唑胺 (TMZ) 对神经胶质瘤细胞的敏感性和杀伤力。我们总结 GSK621 可能通过激活 AMPK 信号传导来抑制人胶质瘤细胞。这种新型 AMPK 激活剂可能是一种新型且有前途的抗神经胶质瘤细胞药物。
Here, we studied the anti-glioma cell activity by a novel AMP-activated protein kinase (AMPK) activator GSK621. We showed that GSK621 was cytotoxic to human glioma cells (U87MG and U251MG lines), possibly via provoking caspase-dependent apoptotic cell death. Its cytotoxicity was alleviated by caspase inhibitors. GSK621 activated AMPK to inhibit mammalian target of rapamycin (mTOR) and downregulate Tetraspanin 8 (Tspan8) in glioma cells. AMPK inhibition, through shRNA knockdown of AMPKα or introduction of a dominant negative (T172A) AMPKα, almost reversed GSK621-induced AMPK activation, mTOR inhibition and Tspan8 degradation. Consequently, GSK621’s cytotoxicity in glioma cells was also significantly attenuated by AMPKα knockdown or mutation. Further studies showed that GSK621, at a relatively low concentration, significantly potentiated temozolomide (TMZ)’s sensitivity and lethality against glioma cells. We summarized that GSK621 inhibits human glioma cells possibly via activating AMPK signaling. This novel AMPK activator could be a novel and promising anti-glioma cell agent.