Rapamycin prevents cadmium-induced neuronal cell death via targeting both mTORC1 and mTORC2 pathways.
Rapamycin prevents cadmium-induced neuronal cell death via targeting both mTORC1 and mTORC2 pathways.
复制标题
雷帕霉素通过靶向 mTORC1 和 mTORC2 途径预防镉诱导的神经细胞死亡
DOI：
10.1016/j.neuropharm.2015.05.008
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发表时间：
2015-10
影响因子：
4.7
通讯作者：
Huang S
中科院分区：
文献类型：
--
作者：
Xu C;Liu C;Liu L;Zhang R;Zhang H;Chen S;Luo Y;Chen L;Huang S
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-BP1 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, downregulation of S6K1, ectopic expression of constitutively hypophosphorylated 4E-BP1 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. It is unclear how inhibition of mTOR by rapamycin prevents Cd-neuronal cell death. This study underscores that rapamycin prevents neuronal cells from Cd-poisoning, not only by targeting mTORC1-mediated S6K1/4E-BP1 pathways, but also via targeting mTORC2-mediated Akt pathway. The findings highlight that rapamycin may be exploited for prevention of Cd-induced neurodegenerative disorders.
