Akt inhibition-dependent downregulation of the Wnt/β-Catenin Signaling pathway contributes to antimony-induced neurotoxicity

Abstract

Antimony (Sb), as a newly identified nerve poison, can lead to neuronal apoptosis. However, its neurotoxicological mechanisms remain largely unclear. Here, we evaluated the role and regulation of Wnt/β-catenin pathway in Sb-mediated neurotoxicity. Under Sb treatment, β-catenin was dramatically downregulated in vivo and in vitro. Moreover, overexpression of β-catenin effectively attenuated Sb-induced survivin gene expression suppression and subsequent apoptosis in PC12 cells. In addition, Sb stimualted glycogen synthase kinase-3β (GSK-3β) activation, shown as decreased phosphorylation levels at Ser 9 both in PC12 cells and mice brain. Paramacological inhibition of GSK-3β using lithium chloride (LiCl) significantly rescued β-catenin expression. For upstream pathway analysis, we found Sb treatment decreased protein kinase B (Akt) phosphorylation, and Akt activator protected PC12 cells from GSK-3β activation and subsequent β-catenin suppression. In summary, our data provided a novel molecular mechanism of Sb-associated neurotoxicity, namely that Sb induces Wnt/β-catenin pathway suppression through Akt inhibition, thus resulted in neuronal apoptosis.

Keywords: Akt inhibition; Antimony; Neuronal apoptosis; Neurotoxicity; Wnt/β-catenin.