Rapamycin ameliorates cadmium-induced activation of MAPK pathway and neuronal apoptosis by preventing mitochondrial ROS inactivation of PP2A

Neuropharmacology
Chong XuLong Chen

Abstract

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 ap...Continue Reading

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Citations

May 13, 2018·Cell Biology International·Shen TangXiyi Li
Feb 2, 2017·Oncotarget·Chong XuLong Chen
Dec 20, 2019·Artificial Cells, Nanomedicine, and Biotechnology·Wan-Ting XuCheng-Hao Jin
Nov 24, 2020·Metallomics : Integrated Biometal Science·Rui-Feng FanZhen-Yong Wang
Jan 9, 2021·European Journal of Nutrition·Xiao-Dong PeiLi-He Jiang
Aug 8, 2021·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Yilu XuCailing Lu

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