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Celastrol prevents cadmium‐induced neuronal cell death via targeting JNK and PTEN‐Akt/ mTOR network
Author(s) -
Chen Sujuan,
Gu Chenjian,
Xu Chong,
Zhang Jinfei,
Xu Yijiao,
Ren Qian,
Guo Min,
Huang Shile,
Chen Long
Publication year - 2014
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12474
Subject(s) - celastrol , protein kinase b , pi3k/akt/mtor pathway , pten , programmed cell death , microbiology and biotechnology , neuroprotection , chemistry , phosphorylation , kinase , signal transduction , biology , cancer research , apoptosis , pharmacology , biochemistry
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 ( p hosphatase and ten sin homolog). The findings suggest that celastrol may be exploited for the prevention of Cd‐induced neurodegenerative disorders.