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Hydrogen peroxide inhibits mTOR signaling by activation of AMPKα leading to apoptosis of neuronal cells
Open accessAbstract
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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“ROS have been shown to activate proinflammatory and MAPK signaling cascades, subsequently leading to various biological responses including cell death or dysfunction [43–45].”
From Nrf2 in keratinocytes modulates UVB-induced DNA damage and apoptosis in melanocytes through MAPK signaling (2017) · cites this paper as [44]
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Metadata
- 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
- Venue
- Laboratory Investigation
- Publisher
- Elsevier BV
- Published
- 2010-05
- Volume
- 90
- Issue
- 5
- Pages
- 762-773
- ISSN
- 0023-6837 (ISSN-L)
- 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
- 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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