title: Cadmium induction of reactive oxygen species activates the mTOR pathway, leading to neuronal cell death.
abstract: Cadmium (Cd), a highly toxic environmental pollutant, induces neurodegenerative diseases. Recently we have demonstrated that Cd induces neuronal apoptosis in part through activation of the mammalian target of rapamycin (mTOR) pathway. However, the underlying mechanism is unknown. Here we show that Cd induces the generation of reactive oxygen species (ROS) by upregulating the expression of NADPH oxidase 2 and its regulatory proteins (p22(phox), p67(phox), p40(phox), p47(phox), and Rac1) in PC12 and SH-SY5Y cells. Cd induction of ROS contributed to the activation of mTOR signaling, as pretreatment with N-acetyl-l-cysteine (NAC), a ROS scavenger, prevented this event. Further studies reveal that Cd induction of ROS increased phosphorylation of the type I insulin-like growth factor receptor (IGFR) β subunit, which was abrogated by NAC. Wortmannin, a phosphoinositide 3'-kinase (PI3K) inhibitor, partially attenuated Cd-induced phosphorylation of Akt, p70 S6 kinase 1, and eukaryotic initiation factor 4E-binding protein 1, as well as apoptosis of the neuronal cells. In addition, overexpression of wild-type phosphatase and tensin homologue deleted on chromosome 10 (PTEN) or pretreatment with aminoimidazole carboxamide ribonucleotide, an AMP-activated protein kinase (AMPK) activator, partially prevented Cd-induced ROS and activation of the mTOR pathway, as well as cell death. The results indicate that Cd induction of ROS activates mTOR signaling, leading to neuronal cell death, in part by activating the positive regulators IGFR/PI3K and by inhibiting the negative regulators PTEN/AMPK. The findings suggest that inhibitors of PI3K and mTOR, activators of AMPK, or antioxidants may be exploited for the prevention of Cd-induced neurodegenerative diseases.
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA.
authors.forename: Long
authors.initials: L
authors.lastname: Chen
authors.forename: Baoshan
authors.initials: B
authors.lastname: Xu
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhou
authors.forename: Wenxing
authors.initials: W
authors.lastname: Chen
authors.forename: Tao
authors.initials: T
authors.lastname: Shen
authors.forename: Xiuzhen
authors.initials: X
authors.lastname: Han
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Kontos
authors.forename: Shile
authors.initials: S
authors.lastname: Huang
mesh_terms: D000111:Acetylcysteine / Q000032:analysis; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002104:Cadmium / Q000633:toxicity*; D002352:Carrier Proteins / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity*; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019255:NADPH Oxidases / Q000235:genetics / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D016716:PC12 Cells; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017451:Receptors, Somatomedin / Q000235:genetics; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000077191:Wortmannin; D020830:rac1 GTP-Binding Protein / Q000235:genetics
chemical_list: D000730:Androstadienes; D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D004785:Environmental Pollutants; D047908:Intracellular Signaling Peptides and Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D017451:Receptors, Somatomedin; C085072:neutrophil cytosol factor 40K; C079789:neutrophil cytosol factor 67K; D002104:Cadmium; D019255:NADPH Oxidases; C086986:CYBA protein, human; C060505:neutrophil cytosolic factor 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020830:rac1 GTP-Binding Protein; D000111:Acetylcysteine; D000077191:Wortmannin