PMID- 21195169
OWN - NLM
STAT- MEDLINE
DCOM- 20110506
LR  - 20211203
IS  - 1873-4596 (Electronic)
IS  - 0891-5849 (Print)
IS  - 0891-5849 (Linking)
VI  - 50
IP  - 5
DP  - 2011 Mar 1
TI  - Cadmium induction of reactive oxygen species activates the mTOR pathway, leading 
      to neuronal cell death.
PG  - 624-32
LID - 10.1016/j.freeradbiomed.2010.12.032 [doi]
AB  - 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) beta 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.
CI  - 2010 Elsevier Inc. All rights reserved.
FAU - Chen, Long
AU  - Chen L
AD  - Department of Biochemistry and Molecular Biology, Louisiana State University 
      Health Sciences Center, Shreveport, LA 71130-3932, USA.
FAU - Xu, Baoshan
AU  - Xu B
FAU - Liu, Lei
AU  - Liu L
FAU - Luo, Yan
AU  - Luo Y
FAU - Zhou, Hongyu
AU  - Zhou H
FAU - Chen, Wenxing
AU  - Chen W
FAU - Shen, Tao
AU  - Shen T
FAU - Han, Xiuzhen
AU  - Han X
FAU - Kontos, Christopher D
AU  - Kontos CD
FAU - Huang, Shile
AU  - Huang S
LA  - eng
GR  - R01 CA115414/CA/NCI NIH HHS/United States
GR  - R01 CA115414-04/CA/NCI NIH HHS/United States
GR  - CA115414/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20101230
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - 0 (Androstadienes)
RN  - 0 (Carrier Proteins)
RN  - 0 (Eif4ebp1 protein, rat)
RN  - 0 (Environmental Pollutants)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Phosphoproteins)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Receptors, Somatomedin)
RN  - 0 (neutrophil cytosol factor 40K)
RN  - 0 (neutrophil cytosol factor 67K)
RN  - 00BH33GNGH (Cadmium)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 1.6.3.1 (CYBA protein, human)
RN  - EC 1.6.3.1 (neutrophil cytosolic factor 1)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.6.5.2 (rac1 GTP-Binding Protein)
RN  - WYQ7N0BPYC (Acetylcysteine)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Acetylcysteine/analysis
MH  - Androstadienes/pharmacology
MH  - Animals
MH  - Apoptosis/*drug effects
MH  - Cadmium/*toxicity
MH  - Carrier Proteins/metabolism
MH  - Environmental Pollutants/*toxicity
MH  - Gene Expression Regulation
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins
MH  - NADPH Oxidases/genetics/physiology
MH  - Neurodegenerative Diseases/chemically induced/metabolism/pathology
MH  - Neurons/*drug effects/pathology
MH  - PC12 Cells
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphoproteins/genetics/metabolism
MH  - Phosphorylation
MH  - Rats
MH  - Reactive Oxygen Species/*metabolism
MH  - Receptors, Somatomedin/genetics
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Wortmannin
MH  - rac1 GTP-Binding Protein/genetics
PMC - PMC3032035
MID - NIHMS262082
EDAT- 2011/01/05 06:00
MHDA- 2011/05/07 06:00
PMCR- 2012/03/01
CRDT- 2011/01/04 06:00
PHST- 2010/09/10 00:00 [received]
PHST- 2010/12/04 00:00 [revised]
PHST- 2010/12/21 00:00 [accepted]
PHST- 2011/01/04 06:00 [entrez]
PHST- 2011/01/05 06:00 [pubmed]
PHST- 2011/05/07 06:00 [medline]
PHST- 2012/03/01 00:00 [pmc-release]
AID - S0891-5849(10)01464-4 [pii]
AID - 10.1016/j.freeradbiomed.2010.12.032 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2011 Mar 1;50(5):624-32. doi: 
      10.1016/j.freeradbiomed.2010.12.032. Epub 2010 Dec 30.