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

Abrar Ul Haq Khan, Moeez G. Rathore, Nerea Allende-Vega, Dang Nghiem Vo, Sana Belkhala, Stefania Orecchioni, Giovanna Talarico, Francesco Bertolini, Guillaume Cartron, Charles Henri Lecellier, Martin Villalba

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21 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)43-53
Number of pages11
JournalEBioMedicine
Volume3
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

Keywords

  • Antioxidant response elements (ARE)
  • ERK5
  • MEF2
  • Mitochondria
  • Oxidative phosphorylation (OXPHOS)
  • miR-23

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    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. (2016). Human Leukemic Cells performing Oxidative Phosphorylation (OXPHOS) Generate an Antioxidant Response Independently of Reactive Oxygen species (ROS) Production. EBioMedicine, 3, 43-53. https://doi.org/10.1016/j.ebiom.2015.11.045