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