Cited by 236PI3K/AKT/mTOR signaling in cancerRedox biology and oxidative stressAutophagy in Disease and Therapy

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Hydrogen peroxide inhibits mTOR signaling by activation of AMPKα leading to apoptosis of neuronal cells

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Chen, Long, Xu, Baoshan, Liu, Lei, Luo, Yan, Yin, Jun, Zhou, Hongyu, Chen, Wenxing, Shen, Tao, Han, Xiuzhen, Huang, Shile·2010·Laboratory Investigation

DOI 10.1038/labinvest.2010.36PMC PMC2861733

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Abstract

Oxidative stress results in apoptosis of neuronal cells, leading to neurodegenerative disorders. However, the underlying molecular mechanism remains to be elucidated. Here, we show that hydrogen peroxide (H(2)O(2)), a major oxidant generated when oxidative stress occurs, induced apoptosis of neuronal cells (PC12 cells and primary murine neurons), by inhibiting the mammalian target of rapamycin (mTOR)-mediated phosphorylation of ribosomal p70 S6 kinase (S6K1) and eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1). N-acetyl-L-cysteine (NAC), a scavenger of reactive oxygen species (ROS), blocked H(2)O(2) inhibition of mTOR signaling. Ectopic expression of wild-type (wt) mTOR, constitutively active S6K1 or downregulation of 4E-BP1 partially prevented H(2)O(2) induction of apoptosis. Furthermore, we identified that H(2)O(2) induction of ROS inhibited the upstream kinases, Akt and phosphoinositide-dependent kinase 1 (PDK1), but not the type I insulin-like growth factor receptor (IGFR), and activated the negative regulator, AMP-activated protein kinase alpha (AMPKalpha), but not the phosphatase and tensin homolog (PTEN) in the cells. Expression of a dominant negative AMPKalpha or downregulation of AMPKalpha1 conferred partial resistance to H(2)O(2) inhibition of phosphorylation of S6K1 and 4E-BP1, as well as cell viability, indicating that H(2)O(2) inhibition of mTOR signaling is at least in part through activation of AMPK. Our findings suggest that AMPK inhibitors may be exploited for prevention of H(2)O(2)-induced neurodegenerative diseases.

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Authors: Chen, L., Xu, B., Liu, L., Luo, Y., Yin, J., Zhou, H., Chen, W., Shen, T., Han, X., & Huang, S.
Affiliations: Louisiana State University Health Sciences Center Shreveport (US)
Feist-Weiller Cancer Center (US)
Corresponding author: Huang, Shile
ORCID: Chen, Long
Xu, Baoshan
Liu, Lei
Luo, Yan
Yin, Jun
Zhou, Hongyu
Chen, Wenxing
Shen, Tao
Han, Xiuzhen
Huang, Shile
Venue: Laboratory Investigation
Publisher: Elsevier BV
Published: 2010-05
Volume: 90
Issue: 5
Pages: 762-773
ISSN: 0023-6837 (ISSN-L)
DOI: 10.1038/labinvest.2010.36
PMC: PMC2861733
OpenAlex: W2062195516
Cited by: 236
References: 49
Citations by year: 2026: 6 · 2025: 9 · 2024: 11 · 2023: 8 · 2022: 10 · 2021: 16 · 2020: 16 · 2019: 11 · 2018: 17 · 2017: 18 · 2016: 19 · 2015: 17 · 2014: 20 · 2013: 21 · 2012: 15
FWCI: 7.55
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 4638 d)
Locations: Laboratory Investigation (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Science Foundation
Louisiana State University
National Institutes of Health
National Cancer Institute (R01CA115414, CA115414)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Keywords: hydrogen peroxide, mTOR signaling, AMPKα, neuronal apoptosis, oxidative stress, S6K1 phosphorylation, 4E-BP1, reactive oxygen species, Akt, PDK1, neurodegenerative diseases, N-acetylcysteine, PC12 cells, primary neurons
MeSH terms: Animals, Cell Line, Cells, Cultured, Enzyme Activation, Humans, Hydrogen Peroxide, Neurons, Phosphoproteins, Phosphorylation, Blotting, Western, Signal Transduction, PC12 Cells, Oxidants, Apoptosis, Protein Serine-Threonine Kinases, Reactive Oxygen Species, Ribosomal Protein S6 Kinases, RNA Interference, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, Mice, Rats, AMP-Activated Protein Kinases, TOR Serine-Threonine Kinases

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Hydrogen peroxide inhibits mTOR signaling by activation of AMPKα leading to apoptosis of neuronal cells

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