Rapamycin inhibits Erk1/2-mediated neuronal apoptosis caused by cadmium

// Chong Xu 1, * , Hai Zhang 1, * , Chunxiao Liu 1 , Yu Zhu 1 , Xiaoxue Wang 1 , Wei Gao 1 , Shile Huang 2, 3 , Long Chen 1 1 Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, PR China 2 Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA 3 Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, USA * These authors have contributed equally to this work Correspondence to: Long Chen, e-mail: lchen@njnu.edu.cn Shile Huang, e-mail: shuan1@lsuhsc.edu Keywords: rapamycin, neuronal apoptosis, PP2A, PTEN, Erk1/2 Received: March 11, 2015      Accepted: May 11, 2015      Published: May 25, 2015 ABSTRACT Cadmium (Cd), an environmental contaminant, causes neurodegenerative disorders. Recently we have shown that rapamycin prevents Cd-induced neuronal cell death by inhibiting mTOR signaling pathway. Here we found that rapamycin exerted its prevention against Cd-induced neuronal cell death also partially via blocking Erk1/2 pathway. Inhibiting Erk1/2 with PD98059 or silencing Erk1/2 potentiated rapamycin’s inhibition of Cd-induced phosphorylation of Erk1/2 and apoptosis in neuronal cells. Both PP2A and PTEN/Akt were involved in the regulation of Erk1/2 activation and cell death triggered by Cd. Inhibition of PP2A with okadaic acid or ectopic expression of dominant negative PP2A attenuated rapamycin’s inhibition of Cd-induced phospho-Erk1/2 and apoptosis, whereas over-expression of wild-type PP2A enhanced rapamycin’s effects; Over-expression of wild-type PTEN or dominant negative Akt, or inhibition of Akt with Akt inhibitor X strengthened rapamycin’s inhibition of Cd-induced phospho-Erk1/2 and cell death. Furthermore, expression of a rapamycin-resistant and kinase-active mTOR (mTOR-T) blocked rapamycin’s inhibitory effects on Cd-induced inhibition of PP2A, down-regulation of PTEN, and activation of Akt, leading to Erk1/2 activation and cell death, whereas silencing mTOR mimicked rapamycin’s effects. The results uncover that rapamycin inhibits Cd activation of Erk1/2-mediated neuronal apoptosis through intervening mTOR-PP2A/PTEN signaling network.