title: Human Leukemic Cells performing Oxidative Phosphorylation (OXPHOS) Generate an Antioxidant Response Independently of Reactive Oxygen species (ROS) Production.
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.
authors: INSERM, U1183; Université de Montpellier 1, UFR Medecine, 80, Av. Augustin Fliche, 34295 Montpellier Cedex 5, France.
authors: Abrar Ul Haq
authors: AUH
authors: Khan
authors: INSERM, U1183; Université de Montpellier 1, UFR Medecine, 80, Av. Augustin Fliche, 34295 Montpellier Cedex 5, France.
authors: Moeez G
authors: MG
authors: Rathore
authors: INSERM, U1183; Université de Montpellier 1, UFR Medecine, 80, Av. Augustin Fliche, 34295 Montpellier Cedex 5, France.
authors: Nerea
authors: N
authors: Allende-Vega
authors: INSERM, U1183; Université de Montpellier 1, UFR Medecine, 80, Av. Augustin Fliche, 34295 Montpellier Cedex 5, France.
authors: Dang-Nghiem
authors: DN
authors: Vo
authors: INSERM, U1183; Université de Montpellier 1, UFR Medecine, 80, Av. Augustin Fliche, 34295 Montpellier Cedex 5, France.
authors: Sana
authors: S
authors: Belkhala
authors: Laboratory of Hematology-Oncology, European Institute of Oncology, Milan, Italy.
authors: Stefania
authors: S
authors: Orecchioni
authors: Laboratory of Hematology-Oncology, European Institute of Oncology, Milan, Italy.
authors: Giovanna
authors: G
authors: Talarico
authors: Laboratory of Hematology-Oncology, European Institute of Oncology, Milan, Italy.
authors: Francesco
authors: F
authors: Bertolini
authors: Département d'Hématologie Clinique, CHU Montpellier, Université Montpellier I, 80 Av. Augustin Fliche, 34295 Montpellier, France.
authors: Guillaume
authors: G
authors: Cartron
authors: Institut de Génétique Moléculaire de Montpellier, University of Montpellier, France; Institut de Biologie Computationnelle, University of Montpellier, France.
authors: Charles-Henri
authors: CH
authors: Lecellier
authors: INSERM, U1183; Université de Montpellier 1, UFR Medecine, 80, Av. Augustin Fliche, 34295 Montpellier Cedex 5, France; Institute of Regenerative Medicine and Biotherapy (IRMB), CHU Montpellier, Montpellier, 34295, France. Electronic address: martin.villalba@inserm.fr.
authors: Martin
authors: M
authors: Villalba
mesh_terms: D020413:3' Untranslated Regions; D061745:Antioxidant Response Elements; D000975:Antioxidants / Q000378:metabolism*; D045744:Cell Line, Tumor; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D000072019:Kelch-Like ECH-Associated Protein 1; D007938:Leukemia / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism; D008954:Models, Biological; D009928:Organ Specificity / Q000235:genetics; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D034622:RNA Interference; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D000975:Antioxidants; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; C552430:MIRN23a microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D048054:Mitogen-Activated Protein Kinase 7
keywords: Antioxidant response elements (ARE); ERK5; MEF2; Mitochondria; Oxidative phosphorylation (OXPHOS); miR-23