PMID- 24111524 OWN - NLM STAT- MEDLINE DCOM- 20140307 LR - 20211203 IS - 1471-4159 (Electronic) IS - 0022-3042 (Print) IS - 0022-3042 (Linking) VI - 128 IP - 2 DP - 2014 Jan TI - Celastrol prevents cadmium-induced neuronal cell death via targeting JNK and PTEN-Akt/mTOR network. PG - 256-266 LID - 10.1111/jnc.12474 [doi] AB - 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. CI - (c) 2013 International Society for Neurochemistry. FAU - Chen, Sujuan AU - Chen S AD - Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China. FAU - Gu, Chenjian AU - Gu C AD - Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China. FAU - Xu, Chong AU - Xu C AD - Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China. FAU - Zhang, Jinfei AU - Zhang J AD - Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China. FAU - Xu, Yijiao AU - Xu Y AD - Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China. FAU - Ren, Qian AU - Ren Q AD - Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China. FAU - Guo, Min AU - Guo M AD - Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China. FAU - Huang, Shile AU - Huang S AD - Department of Biochemistry and Molecular Biology, Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, Los Angeles, USA. FAU - Chen, Long AU - Chen L AD - Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China. LA - eng GR - R01 CA115414/CA/NCI NIH HHS/United States GR - CA115414/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20131024 PL - England TA - J Neurochem JT - Journal of neurochemistry JID - 2985190R RN - 0 (Environmental Pollutants) RN - 0 (Neuroprotective Agents) RN - 0 (Pentacyclic Triterpenes) RN - 0 (Triterpenes) RN - EC 2.7.1.1 (mTOR protein, rat) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases) RN - EC 3.1.3.67 (PTEN Phosphohydrolase) RN - J6K4F9V3BA (Cadmium Chloride) RN - L8GG98663L (celastrol) SB - IM MH - Animals MH - Apoptosis/drug effects MH - Cadmium Chloride/*toxicity MH - Cell Survival/drug effects MH - Environmental Pollutants/*toxicity MH - JNK Mitogen-Activated Protein Kinases/metabolism MH - Neurons/cytology/*drug effects/metabolism MH - Neuroprotective Agents/*pharmacology MH - PC12 Cells MH - PTEN Phosphohydrolase/metabolism MH - Pentacyclic Triterpenes MH - Proto-Oncogene Proteins c-akt/metabolism MH - Rats MH - Signal Transduction/drug effects MH - TOR Serine-Threonine Kinases/metabolism MH - Triterpenes/*pharmacology PMC - PMC4183230 MID - NIHMS631546 OTO - NOTNLM OT - Celastrol OT - apoptosis OT - c-Jun N-terminal kinase OT - cadmium OT - mammalian target of rapamycin OT - phosphatase and tensin homolog on chromosome 10 EDAT- 2013/10/12 06:00 MHDA- 2014/03/08 06:00 PMCR- 2015/01/01 CRDT- 2013/10/12 06:00 PHST- 2013/08/10 00:00 [received] PHST- 2013/09/16 00:00 [revised] PHST- 2013/09/27 00:00 [accepted] PHST- 2013/10/12 06:00 [entrez] PHST- 2013/10/12 06:00 [pubmed] PHST- 2014/03/08 06:00 [medline] PHST- 2015/01/01 00:00 [pmc-release] AID - 10.1111/jnc.12474 [doi] PST - ppublish SO - J Neurochem. 2014 Jan;128(2):256-266. doi: 10.1111/jnc.12474. Epub 2013 Oct 24.