Neuroprotection of resveratrol against cadmium-poisoning acts through dual inhibition of mTORC1/2 signaling.

Resveratrol is a natural polyphenol with neuroprotective function. The underlying mechanism is not well understood. Our previous studies have identified that resveratrol antagonizes cadmium (Cd) neurotoxicity via targeting PP2A/PP5-mediated Erk1/2 and JNK pathways. Here we show that resveratrol protected against Cd-poisoning also by blocking Cd-induced activation of mTORC1 and mTORC2 pathways in PC12 cells and murine primary neurons. Co-treatment with inhibitors of mTORC1 (rapamycin), mTORC1/2 (PP242), Erk1/2 (U0126) and/or JNK (SP600125), knockdown of mTOR, or disruption of mTORC1 and/or mTORC2 by silencing raptor, rictor or raptor/rictor, respectively, markedly potentiated the inhibitory effects of resveratrol on Cd-induced phosphorylation of S6K1/4E-BP1 (mTORC1 substrates), Akt (mTORC2 substrate), Erk1/2 and/or JNK/c-Jun, cleavage of caspase-3 and cell death in PC12 cells and/or primary neurons. Knockdown of S6K1 or 4E-BP1, or ectopic expression of constitutively hypophosphorylated 4E-BP1 (4E-BP1-5A) reinforced the resveratrol's inhibition on Cd-evoked cell death, whereas ectopic expression of constitutively active S6K1 or knockdown of 4E-BP1 attenuated the resveratrol's inhibition on Cd-induced cell death. Co-treatment with Akt inhibitor or overexpression of dominant negative Akt (dn-Akt) strengthened the resveratrol's suppression on Cd-induced ROS, Erk1/2 activation and apoptosis, whereas overexpression of constitutively active Akt (myr-Akt) conferred high resistance to the resveratrol's inhibitory effects in the neuronal cells. Taken together, the results indicate that resveratrol attenuates Cd-induced neuronal apoptosis partly through inhibition of mTORC1/2 pathways. Our studies highlight that resveratrol can be exploited for the prevention of Cd toxicity related to neurodegenerative diseases.