Cadmium activates the mitogen-activated protein kinase (MAPK) pathway via induction of reactive oxygen species and inhibition of protein phosphatases 2A and 5
Cadmium activates the mitogen-activated protein kinase (MAPK) pathway via induction of reactive oxygen species and inhibition of protein phosphatases 2A and 5
复制标题
DOI：
10.1016/j.freeradbiomed.2008.07.011
复制
发表时间：
2008-10-01
影响因子：
7.4
通讯作者：
Huang, Shile
中科院分区：
文献类型：
--
作者：
Chen, Long;Liu, Lei;Huang, Shile
镉（Cd）是一种毒性很强的环境污染物，可引起神经退行性疾病。近年来研究表明，镉可通过激活c-Jun N-末端激酶（JNK）和细胞外信号调节激酶1/2（Erk 1/2）途径诱导神经元凋亡。然而，潜在的机制仍然是谜。在这里，我们表明，镉诱导产生活性氧（ROS），导致PC 12和SH-SY 5 Y细胞凋亡。N-乙酰-L-半胱氨酸（NAC）预处理可清除Cd诱导的ROS，阻止细胞死亡，提示Cd诱导的细胞凋亡与其诱导ROS有关。此外，我们发现，镉诱导的活性氧抑制丝氨酸/苏氨酸蛋白磷酸酶2A（PP 2A）和5（PP 5），导致激活的Erk 1/2和JNK，这是废除NAC。PP 2A或PP 5的过表达部分地阻止了Cd诱导的Erk 1/2和JNK的激活以及细胞死亡。镉诱导的ROS也与caspase-3的激活有关。用JNK（SP 600125）和Erk 1/2（1-10126）抑制剂预处理可部分阻断Cd诱导的caspase-3的破坏，并防止细胞死亡。然而，zVAD-fastin，一个pail半胱天冬酶抑制剂，只能部分阻止镉诱导的细胞凋亡。结果表明，镉诱导的ROS抑制PP 2A和PP 5，导致JNK和EFk 1/2途径的激活，从而导致caspase依赖性和非依赖性的神经细胞凋亡。研究结果强烈表明，JNK，Erk 1/2，或抗氧化剂的抑制剂可用于预防镉诱导的神经退行性疾病。(C)2008年爱思唯尔公司所有战斗保留。
Cadmium (Cd), a highly toxic environmental pollutant, induces neurodegenerative diseases. Recently we have demonstrated that Cd may induce neuronal apoptosis in part through activation Of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 1/2 (Erk1/2) pathways. However, the underlying mechanism remains enigmatic. Here we show that Cd induced generation of reactive oxygen species (ROS), leading to apoptosis of PC12 and SH-SY5Y cells. Pretreatment with N-acetyl-L-cysteine (NAC) scavenged Cd-induced ROS, and prevented cell death, suggesting that Cd-induced apaptosis is attributed to its induction of ROS. Furthermore, we found that Cd-induced ROS inhibited serine/threonine protein phosphatases 2A (PP2A) and 5 (PP5), leading to activation of Erk1/2 and JNK, which was abrogated by NAC. Overexpression of PP2A or PP5 partially prevented Cd-induced activation of Erk1/2 and JNK, as well as cell death. Cd-induced ROS was also linked to the activation of caspase-3. Pretreatment with inhibitors of JNK (SP600125) and Erk1/2 (1-10126) partially blocked Cd-induced deavage of caspase-3 and prevented cell death. However, zVAD-fmk, a pail caspase inhibitor, only partially prevented Cd-induced apoptosis. The results indicate that Cd induction of ROS inhibits PP2A and PP5, leading to activation of JNK( and EFk1/2 pathways, and consequently resulting in caspase-dependent and -independent apoptosis of neuronal cells. The findings Strongly suggest that the inhibitors of JNK, Erk1/2, or antioxidants may be exploited for prevention of Cd-induced neurodeggenerative diseases. (C) 2008 Elsevier Inc. All Fights reserved.