期刊
NEUROPHARMACOLOGY
卷 97, 期 -, 页码 35-45出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2015.05.008
关键词
Rapamycin; Cadmium; Neuronal cells; Apoptosis; mTOR
资金
- NIH [CA115414]
- National Natural Science Foundation of China [30971486, 81271416]
- American Cancer Society [RSG-08-135-01-CNE]
- Louisiana Board of Regents [NSF-2009-PFUND-144]
- Scientific Research Foundation of the State Education Ministry of China [SEMR20091341]
- Project for the Priority Academic Program Development
- Natural Science Foundation of Jiangsu Higher Education Institutions of China [10KJA180027]
- Innovative Research Program of Jiangsu College Graduate of China [KYLX_L0713]
Cadmium (Cd), a toxic environmental contaminant, contributes to neurodegeneration. Rapamycin, a macrocyclic lactone, has shown preventive effect on Cd-induced neuronal cell death. However, the underlying mechanism is not fully understood. Here, we show that rapamycin prevented Cd-induced apoptotic cell death in neuronal cells. Coincidently, rapamycin markedly blocked Cd-induced phosphorylation of Akt, S6K1 and 4E-BPI in the cells. Expression of a rapamycin-resistant and kinase-active mTOR (S2035T, mTOR-T), but not a rapamycin-resistant and kinase-dead mTOR (S2035T/D2357E, mTOR-TE), conferred resistance to rapamycin inhibition of Cd-induced cell death, implying that the preventive effect of rapamycin on Cd-induced neurotoxicity is mTOR kinase activity-dependent. It appeared that both mTORC1 and mTORC2 were involved in the inhibitory activity of rapamycin, as silencing raptor, rictor or raptor/rictor enhanced rapamycin's blockage of Cd-induced cell death. Furthermore, down-regulation of S6K1, ectopic expression of constitutively hypophosphorylated 4E-BPI or dominant negative Akt, or co-treatment with Akt inhibitor also potentiated the rapamycin's inhibitory effect. The findings indicate that rapamycin prevents Cd-induced neuronal cell death via suppressing both mTORC1 and mTORC2 pathways. Our results highlight that rapamycin may be exploited for the prevention of Cd-induced neurodegenerative disorders. (C) 2015 Elsevier Ltd. All rights reserved.
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