TY - JOUR
T1 - Human Leukemic Cells performing Oxidative Phosphorylation (OXPHOS) Generate an Antioxidant Response Independently of Reactive Oxygen species (ROS) Production
AU - Khan, Abrar Ul Haq
AU - Rathore, Moeez G.
AU - Allende-Vega, Nerea
AU - Vo, Dang Nghiem
AU - Belkhala, Sana
AU - Orecchioni, Stefania
AU - Talarico, Giovanna
AU - Bertolini, Francesco
AU - Cartron, Guillaume
AU - Lecellier, Charles Henri
AU - Villalba, Martin
N1 - Publisher Copyright:
© 2015 The Authors.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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.
AB - 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.
KW - Antioxidant response elements (ARE)
KW - ERK5
KW - MEF2
KW - Mitochondria
KW - Oxidative phosphorylation (OXPHOS)
KW - miR-23
UR - http://www.scopus.com/inward/record.url?scp=84958852021&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84958852021&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2015.11.045
DO - 10.1016/j.ebiom.2015.11.045
M3 - Article
C2 - 26870816
AN - SCOPUS:84958852021
SN - 2352-3964
VL - 3
SP - 43
EP - 53
JO - EBioMedicine
JF - EBioMedicine
ER -
