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Cited by 59Genomics, phytochemicals, and oxidative stressRedox biology and oxidative stressBioactive Compounds and Antitumor Agents

Human Leukemic Cells performing Oxidative Phosphorylation (OXPHOS) Generate an Antioxidant Response Independently of Reactive Oxygen species (ROS) Production

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Khan, Abrar Ul Haq, Rathore, Moeez G., Allende-Vega, Nerea, Vo, Dang-Nghiem, Belkhala, Sana, Orecchioni, Stefania, Talarico, Giovanna, Bertolini, Francesco +3 more·2016·EBioMedicine
DOI 10.1016/j.ebiom.2015.11.045PMC PMC4739420
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Abstract

Tumor cell metabolism is altered during leukemogenesis. Cells performing oxidative phosphorylation (OXPHOS) generate reactive oxygen species (ROS) through mitochondrial activity. To limit the deleterious effects of excess ROS, certain gene promoters contain antioxidant response elements (ARE), e.g. the genes NQO-1 and HO-1. ROS induces conformational changes in KEAP1 and releases NRF2, which activates AREs. We show in vitro and in vivo that OXPHOS induces, both in primary leukemic cells and cell lines, de novo expression of NQO-1 and HO-1 and also the MAPK ERK5 and decreases KEAP1 mRNA. ERK5 activates the transcription factor MEF2, which binds to the promoter of the miR-23a-27a-24-2 cluster. Newly generated miR-23a destabilizes KEAP1 mRNA by binding to its 3'UTR. Lower KEAP1 levels increase the basal expression of the NRF2-dependent genes NQO-1 and HO-1. Hence, leukemic cells performing OXPHOS, independently of de novo ROS production, generate an antioxidant response to protect themselves from ROS.

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  • Expression of miR-23a is restrained by the p65 subunit of NF-κB, confirming that miR-23a is a hub for regulating glutamine metabolism.

    “the expression of miR-23a is restrained by the p65 subunit of NF-κB, confirms that miR-23a is a hub for regulating glutamine metabolism”

    From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [95]

    The Discussion (page unavailable) links miR-23a levels to glutamine metabolism, supporting its regulatory role. But the Results section on miR-23a upregulation identifies ERK5 acting through MEF2; our copy does not establish that NF-κB p65 restrains miR-23a expression. The References list a separate Rathore et al. (2012) paper on p65 and glutamine metabolism, but this paper relies on that work when discussing miR-23a rather than merely mentioning it. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Over-expression of miR-23a reduces expression of its target glutaminase GLS, induces mitochondrial dysfunction, and leads to leukemia cell death.

    “over-expression of miR-23a reduces the expression of its target glutaminase GLS, induces mitochondrial dysfunction, and leads to leukemia cell death”

    From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [95]

    The Discussion states that high miR-23a levels induce cell death through impaired glutamine metabolism and mitochondrial activity. It does not state that miR-23a overexpression reduces GLS expression; the Results instead identify KEAP1 as a direct miR-23a target. Our copy therefore supports the mitochondrial and cell-death portions, but not the specific GLS mechanism. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The miR-23a functional cluster can affect antioxidant response elements by targeting KEAP1, participates in oxidative phosphorylation of tumor cells, and affects mitochondrial activity.

    “the miR-23a functional cluster can affect antioxidant response elements by targeting KEAP1, participates in oxidative phosphorylation of tumor cells, and affects mitochondrial activity [94,95].”

    From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [95]

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Authors
Khan, A. U. H., Rathore, M. G., Allende-Vega, N., Vo, D.-N., Belkhala, S., Orecchioni, S., Talarico, G., Bertolini, F., Cartron, G., Lecellier, C.-H., & Villalba, M.
Affiliations
  • Inserm (FR)
  • European Institute of Oncology (IT)
  • Centre Hospitalier Universitaire de Montpellier (FR)
  • Université de Montpellier (FR)
ORCID
Venue
EBioMedicine
Publisher
Elsevier BV
Published
2016-01
Volume
3
Pages
43-53
ISSN
2352-3964 (ISSN-L)
DOI
10.1016/j.ebiom.2015.11.045
PMC
PMC4739420
OpenAlex
W2172330709
Cited by
59
References
3
Citations by year
2026: 2 · 2025: 8 · 2024: 6 · 2023: 2 · 2022: 10 · 2021: 5 · 2020: 4 · 2019: 6 · 2018: 7 · 2017: 7 · 2016: 2
FWCI
2.32
Type
journal article
Language
en
Open access
Licence
Locations
  • EBioMedicine (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Region Languedoc-Roussillon (09-13195)
  • “Communauté de Travail des Pyrénées” (CTPP5/12)
  • L'Un pour l'Autre and Ensangble (09/2013)
  • European Community Program SUDOE (CLiNK SOE2/P1/E341)
  • CHU Montpellier (No. 221826)
  • Fondation de France (0057921)
  • Région Languedoc Roussillon
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
Keywords
oxidative phosphorylation, leukemia cells, antioxidant response, reactive oxygen species, Keap1, Nrf2, NQO1, heme oxygenase-1, ERK5, MAPK signaling, MEF2, 3' untranslated region, leukemogenesis
MeSH terms
Kelch-Like ECH-Associated Protein 1, Antioxidants, Humans, Leukemia, Mitochondria, Models, Biological, Organ Specificity, Oxidative Phosphorylation, RNA, Messenger, Gene Expression Regulation, Leukemic, Reactive Oxygen Species, Oxidative Stress, 3' Untranslated Regions, RNA Interference, MicroRNAs, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, Mitogen-Activated Protein Kinase 7, Antioxidant Response Elements

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