Journal article
Arsenic Inhibits Neurite Outgrowth by Inhibiting the LKB1–AMPK Signaling Pathway
Environmental health perspectives, Vol.118(5), pp.627-634
05/2010
DOI: 10.1289/ehp.0901510
PMCID: PMC2866677
PMID: 20439172
Abstract
Background: Arsenic (As) is an environmental pollutant that induces numerous pathological effects, including neurodevelopmental disorders.
Objectives and methods: We evaluated the role of the LKB1-AMPK pathway in As-induced developmental neurotoxicity using Neuro-2a (N2a) neuroblastoma cells as a model of developing neurons.
Results: The addition of low concentrations of As (<or= 5 microM) during differentiation caused an inhibitory effect on the neurite outgrowth in N2a cells in the absence of cell death. Activation of adenosine monophosphate-activated kinase (AMPK) induced by retinoic acid in differentiating cells was blocked by As. Pretreatment with the AMPK-specific activator 5-aminoimidazole-4-carboxamide riboside or overexpression of a constitutively active AMPK-alpha1 plasmid reversed As-induced inhibition of neurite outgrowth. The activation of LKB1 (serine/threonine kinase 11), a major AMPK kinase, was also suppressed by As by inhibiting both the phosphorylation and the translocation of LKB1 from nucleus to cytoplasm. Antioxidants, such as N-acetyl cysteine and superoxide dismutase, but not catalase, protected against As-induced inactivation of the LKB1-AMPK pathway and reversed the inhibitory effect of As on neurite outgrowth.
Conclusions: Reduced neurite outgrowth induced by As results from deficient activation of AMPK as a consequence of a lack of activation of LKB1. Oxidative stress induced by As, especially excessive superoxide, plays a critical role in blocking the LKB1-AMPK pathway. Our studies provide insight into the mechanisms underlying As-induced developmental neurotoxicity, which is important for designing a new strategy for protecting children against this neurotoxic substance.
Details
- Title: Subtitle
- Arsenic Inhibits Neurite Outgrowth by Inhibiting the LKB1–AMPK Signaling Pathway
- Creators
- Xin Wang - University of KentuckyDan Meng - Shanghai Institutes for Biological SciencesQingshan Chang - University of KentuckyJingju Pan - University of KentuckyZhuo Zhang - University of KentuckyGang Chen - University of KentuckyZunji Ke - Shanghai Institutes for Biological SciencesJia Luo - University of KentuckyXianglin Shi - University of Kentucky
- Resource Type
- Journal article
- Publication Details
- Environmental health perspectives, Vol.118(5), pp.627-634
- Publisher
- National Institute of Environmental Health Sciences
- DOI
- 10.1289/ehp.0901510
- PMID
- 20439172
- PMCID
- PMC2866677
- ISSN
- 0091-6765
- eISSN
- 1552-9924
- Language
- English
- Date published
- 05/2010
- Academic Unit
- Pathology
- Record Identifier
- 9984186674402771
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