Rapamycin prevents cadmium-induced neuronal cell death via targeting both mTORC1 and mTORC2 pathways
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.