Rapamycin ameliorates cadmium-induced activation of MAPK pathway and neuronal apoptosis by preventing mitochondrial ROS inactivation of PP2A.
Rapamycin ameliorates cadmium-induced activation of MAPK pathway and neuronal apoptosis by preventing mitochondrial ROS inactivation of PP2A.
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DOI：
10.1016/j.neuropharm.2016.01.030
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发表时间：
2016-06
影响因子：
4.7
通讯作者：
Chen L
中科院分区：
文献类型：
--
作者：
Xu C;Wang X;Zhu Y;Dong X;Liu C;Zhang H;Liu L;Huang S;Chen L
镉 (Cd) 是一种剧毒金属，会影响中枢神经系统。最近我们已经证明，雷帕霉素抑制 mTOR 可以挽救神经元细胞免受镉中毒。在这里，我们发现雷帕霉素抑制 Cd 诱导的线粒体 ROS 依赖性神经元凋亡。有趣的是，雷帕霉素显着阻断了 Cd 诱导的神经元细胞中 JNK、Erk1/2 和 p38 的磷酸化，并且与 Mito-TEMPO 共同处理可增强这种磷酸化。 SP600125 和 U0126 分别抑制 JNK 和 Erk1/2，增强了雷帕霉素对 Cd 诱导的细胞凋亡的预防作用。一致地，显性失活 c-Jun 或 MKK1 的过度表达也有效改善了雷帕霉素对 Cd 神经毒性的抑制作用。此外，用SP600125或U0126预处理，或显性失活c-Jun或MKK1的表达增强了雷帕霉素或Mito-TEMPO对Cd诱导的ROS的抑制作用。进一步研究发现，与单独使用雷帕霉素或 Mito-TEMPO 处理相比，Mito-TEMPO/雷帕霉素联合处理可通过防止 PP2A 的 Cd 失活更有效地拯救细胞。野生型 PP2A 的过度表达增强了雷帕霉素或 Mito-TEMPO 对激活的 JNK 和 Erk1/2 通路的抑制，以及神经元细胞响应 Cd 的 ROS 产生和凋亡。研究结果表明，雷帕霉素通过防止 PP2A 线粒体 ROS 失活，从而抑制 JNK 和 Erk1/2 通路的激活，从而改善 Cd 诱发的神经元凋亡。我们的结果强调，雷帕霉素可能具有预防镉诱导的氧化应激和神经退行性疾病的潜力。目前尚不清楚雷帕霉素是否以及如何通过干预 ROS 依赖性 MAPK 通路激活来预防 Cd 诱导的神经元凋亡。这项研究发现，雷帕霉素通过防止线粒体 ROS PP2A 失活，从而抑制 JNK 和 Erk1/2 通路的激活，从而改善 Cd 诱发的神经元凋亡。研究结果强调，雷帕霉素可能作为预防镉诱导的氧化应激和神经退行性疾病的潜在治疗剂。
Cadmium (Cd) is a highly toxic metal that affects the central nervous system. Recently we have demonstrated that inhibition of mTOR by rapamycin rescues neuronal cells from Cd-poisoning. Here we show that rapamycin inhibited Cd-induced mitochondrial ROS-dependent neuronal apoptosis. Intriguingly, rapamycin remarkably blocked phosphorylation of JNK, Erk1/2 and p38 in neuronal cells induced by Cd, which was strengthened by co-treatment with Mito-TEMPO. Inhibition of JNK and Erk1/2 by SP600125 and U0126, respectively, potentiated rapamycin’s prevention from Cd-induced apoptosis. Consistently, over-expression of dominant negative c-Jun or MKK1 also potently improved the inhibitory effect of rapamycin on Cd neurotoxicity. Furthermore, pretreatment with SP600125 or U0126, or expression of dominant negative c-Jun or MKK1 enhanced the inhibitory effects of rapamycin or Mito-TEMPO on Cd-induced ROS. Further investigation found that co-treatment with Mito-TEMPO/rapamycin more effectively rescued cells by preventing Cd inactivation of PP2A than treatment with rapamycin or Mito-TEMPO alone. Over-expression of wild-type PP2A reinforced rapamycin or Mito-TEMPO suppression of activated JNK and Erk1/2 pathways, as well as ROS production and apoptosis in neuronal cells in response to Cd. The findings indicate that rapamycin ameliorates Cd-evoked neuronal apoptosis by preventing mitochondrial ROS inactivation of PP2A, thereby suppressing activation of JNK and Erk1/2 pathways. Our results underline that rapamycin may have a potential in preventing Cd-induced oxidative stress and neurodegenerative diseases. It is unclear whether and how rapamycin prevents Cd-induced neuronal apoptosis by intervening ROS-dependent activation of MAPK pathway. This study uncovers that rapamycin ameliorates Cd-evoked neuronal apoptosis by preventing mitochondrial ROS inactivation of PP2A, thereby suppressing activation of JNK and Erk1/2 pathways. The findings highlight that rapamycin may act as a potential therapeutic agent in the prevention of Cd-induced oxidative stress and neurodegenerative diseases.