These authors contributed equally to this study.
Celastrol prevents cadmium-induced neuronal cell death via targeting JNK and PTEN-Akt/mTOR network
Article first published online: 24 OCT 2013
© 2013 International Society for Neurochemistry
Journal of Neurochemistry
Volume 128, Issue 2, pages 256–266, January 2014
How to Cite
J. Neurochem. (2014) 128, 256–266.
- Issue published online: 6 JAN 2014
- Article first published online: 24 OCT 2013
- Accepted manuscript online: 1 OCT 2013 12:01PM EST
- Manuscript Accepted: 27 SEP 2013
- Manuscript Revised: 16 SEP 2013
- Manuscript Received: 10 AUG 2013
- National Natural Science Foundation of China. Grant Numbers: 30971486, 81271416
- NIH. Grant Number: CA115414
- American Cancer Society. Grant Number: RSG-08-135-01-CNE
- Priority Academic Program Development and Natural Science Foundation of Jiangsu Higher Education Institutions of China
- Project for the Priority Academic Program Development
- Natural Science Foundation of Jiangsu Higher Education Institutions of China. Grant Number: 10KJA180027
- Louisiana Board of Regents. Grant Number: NSF-2009-PFUND-144
- Innovative Research Program of Jiangsu College Graduate of China. Grant Number: CXZZ11-0888
- c-Jun N-terminal kinase;
- mammalian target of rapamycin;
- phosphatase and tensin homolog on chromosome 10
Cadmium (Cd), a toxic environmental contaminant, induces neurodegenerative diseases. Celastrol, a plant-derived triterpene, has shown neuroprotective effects in various disease models. However, little is known regarding the effect of celastrol on Cd-induced neurotoxicity. Here, we show that celastrol protected against Cd-induced apoptotic cell death in neuronal cells. This is supported by the findings that celastrol strikingly attenuated Cd-induced viability reduction, morphological change, nuclear fragmentation, and condensation, as well as activation of caspase-3 in neuronal cells. Concurrently, celastrol remarkably blocked Cd-induced phosphorylation of c-Jun N-terminal kinase (JNK), but not extracellular signal-regulated kinases 1/2 and p38, in neuronal cells. Inhibition of JNK by SP600125 or over-expression of dominant negative c-Jun potentiated celastrol protection against Cd-induced cell death. Furthermore, pre-treatment with celastrol prevented Cd down-regulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and activation of phosphoinositide 3′-kinase/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling in neuronal cells. Over-expression of wild-type PTEN enhanced celastrol inhibition of Cd-activated Akt/mTOR signaling and cell death in neuronal cells. The findings indicate that celastrol prevents Cd-induced neuronal cell death via targeting JNK and PTEN-Akt/mTOR network. Our results strongly suggest that celastrol may be exploited for the prevention of Cd-induced neurodegenerative disorders.
Celastrol, a plant-derived triterpene, has shown neuroprotective effects. However, little is known regarding the effect of celastrol on cadmium (Cd) neurotoxicity. This study underscores that celastrol prevents Cd-induced neuronal apoptosis via inhibiting activation of JNK (c-Jun N-terminal kinase) and Akt/mTOR network. Celastrol suppresses Cd-activated Akt/mTOR pathway by elevating PTEN (phosphatase and tensin homolog). The findings suggest that celastrol may be exploited for the prevention of Cd-induced neurodegenerative disorders.