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

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 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.

H2O2 induces PP2A demethylation to downregulate mTORC1 signaling in HEK293 cells

“…These results further support that inhibiting PP2A demethylation induced by oxidative stress rescues mTORC1 signaling inhibition. To further test the effect of LCMT1 overexpression on mTORC1 signaling, we used another mTORC1 inhibitor rapamycin, which is known to downregulate mTORC1 signaling through PP2A Li et al, 2013;Xu et al, 2016), to treat cells and measure activation of mTORC1 signaling. Consistently, we found that rapamycin significantly inhibited mTORC1 activity.…”

Cantharidic acid induces apoptosis through the p38 MAPK signaling pathway in human hepatocellular carcinoma

“…However, the exact effect of CA on HCC is still unknown. Recent studies demonstrate that inhibition of protein phosphatase 2A (PP2A) activity has been linked to mitogen‐activated protein kinase (MAPK) activation and caspase‐3 cleavage‐associated apoptosis . Liu et al also reported that PP2A‐mediated cross‐talk between MAPK ERK and p38 in apoptosis of cardiac ventricular myocytes .…”

Capsular Polysaccharide of Mycoplasma ovipneumoniae Induces Sheep Airway Epithelial Cell Apoptosis via ROS‐Dependent JNK/P38 MAPK Pathways

“…The MAPKs signaling is believed to be involved in the regulation of several signal transduction pathways including cell proliferation, migration, differentiation, autophagy, and apoptosis [8, 38]. MAPKs are evolutionarily conserved Ser/Thr protein kinases that are divided into at least three distinct groups in mammals, including the extracellular signal regulated kinase (ERK), the Jun N-terminal kinases (JNK), and the P38 MAPKs [39].…”