Chen Long, Liu Lei, Luo Yan, Huang Shile
Department of Biochemistry and Molecular Biology and Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932, USA.
J Neurochem. 2008 Apr;105(1):251-61. doi: 10.1111/j.1471-4159.2007.05133.x. Epub 2007 Nov 16.
Cadmium (Cd) may be accumulated in human body through long-term exposure to Cd-polluted environment, resulting in neurodegeneration and other diseases. To study the mechanism of Cd-induced neurodegeneration, PC12 and SH-SY5Y cells were exposed to Cd. We observed that Cd-induced apoptosis in the cells in a time- and concentration-dependent manner. Cd rapidly activated the mitogen-activated protein kinases (MAPK) including extracellular signal-regulated kinase 1/2 (Erk1/2), c-Jun N-terminal kinase (JNK) and p38. Inhibition of Erk1/2 and JNK, but not p38, partially protected the cells from Cd-induced apoptosis. Consistently, over-expression of dominant negative c-Jun or down-regulation of Erk1/2, but not p38 MAPK, partially prevented Cd-induced apoptosis. To our surprise, Cd also activated mammalian target of rapamycin (mTOR)-mediated signaling pathways. Treatment with rapamycin, an mTOR inhibitor, blocked Cd-induced phosphorylation of S6K1 and eukaryotic initiation factor 4E binding protein 1, and markedly inhibited Cd-induced apoptosis. Down-regulation of mTOR by RNA interference also in part, rescued cells from Cd-induced death. These findings indicate that activation of the signaling network of MAPK and mTOR is associated with Cd-induced neuronal apoptosis. Our results strongly suggest that inhibitors of MAPK and mTOR may have a potential for prevention of Cd-induced neurodegeneration.
镉（Cd）可通过长期暴露于镉污染环境而在人体中蓄积，导致神经退行性变及其他疾病。为研究镉诱导神经退行性变的机制，将PC12和SH-SY5Y细胞暴露于镉。我们观察到镉以时间和浓度依赖性方式诱导细胞凋亡。镉迅速激活丝裂原活化蛋白激酶（MAPK），包括细胞外信号调节激酶1/2（Erk1/2）、c-Jun氨基末端激酶（JNK）和p38。抑制Erk1/2和JNK，而非p38，可部分保护细胞免受镉诱导的凋亡。同样，显性负性c-Jun的过表达或Erk1/2的下调，而非p38 MAPK，可部分阻止镉诱导的凋亡。令我们惊讶的是，镉还激活雷帕霉素靶蛋白（mTOR）介导的信号通路。用mTOR抑制剂雷帕霉素处理可阻断镉诱导的S6K1和真核起始因子4E结合蛋白1的磷酸化，并显著抑制镉诱导的凋亡。通过RNA干扰下调mTOR也可部分挽救细胞免于镉诱导的死亡。这些发现表明MAPK和mTOR信号网络的激活与镉诱导的神经元凋亡有关。我们的结果强烈提示MAPK和mTOR抑制剂可能具有预防镉诱导的神经退行性变的潜力。
