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

Overview

Journal EBioMedicine

Specialty Biomedical Engineering

Date 2016 Feb 13

PMID 26870816

Citations 33

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

Recent advances of miR-23 in human diseases and growth development.

Qian X, Jiang Y, Yang Y, Zhang Y, Xu N, Xu B Noncoding RNA Res. 2025; 11:220-233.

PMID: 39896346 PMC: 11787465. DOI: 10.1016/j.ncrna.2024.12.010.

A Systematic Review on Advances in Management of Oxidative Stress-Associated Cardiovascular Diseases.

Jin S, Kang P Antioxidants (Basel). 2024; 13(8).

PMID: 39199169 PMC: 11351257. DOI: 10.3390/antiox13080923.

: An Underexplored p53 Target Gene Linking Glycosylation and Cancer Progression.

Hu D, Kobayashi N, Ohki R Cancers (Basel). 2024; 16(15).

PMID: 39123480 PMC: 11311387. DOI: 10.3390/cancers16152753.

Transcriptome and machine learning analysis of the impact of COVID-19 on mitochondria and multiorgan damage.

Chang Y, Wei A PLoS One. 2024; 19(1):e0297664.

PMID: 38295140 PMC: 10830027. DOI: 10.1371/journal.pone.0297664.

SHARPIN Enhances Ferroptosis in Synovial Sarcoma Cells via NF-κB- and PRMT5-Mediated PGC1α Reduction.

Tamiya H, Urushihara N, Shizuma K, Ogawa H, Nakai S, Wakamatsu T Cancers (Basel). 2023; 15(13).

PMID: 37444594 PMC: 10341212. DOI: 10.3390/cancers15133484.

References

Devasagayam T, Tilak J, Boloor K, Sane K, Ghaskadbi S, Lele R . Free radicals and antioxidants in human health: current status and future prospects. J Assoc Physicians India. 2005; 52:794-804. View

Charni S, de Bettignies G, Rathore M, Aguilo J, van den Elsen P, Haouzi D . Oxidative phosphorylation induces de novo expression of the MHC class I in tumor cells through the ERK5 pathway. J Immunol. 2010; 185(6):3498-503. DOI: 10.4049/jimmunol.1001250. View

Reitzer L, Wice B, Kennell D . Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells. J Biol Chem. 1979; 254(8):2669-76. View

Jezek P, Plecita-Hlavata L, Smolkova K, Rossignol R . Distinctions and similarities of cell bioenergetics and the role of mitochondria in hypoxia, cancer, and embryonic development. Int J Biochem Cell Biol. 2009; 42(5):604-22. DOI: 10.1016/j.biocel.2009.11.008. View

Rushworth S, MacEwan D . The role of nrf2 and cytoprotection in regulating chemotherapy resistance of human leukemia cells. Cancers (Basel). 2013; 3(2):1605-21. PMC: 3757381. DOI: 10.3390/cancers3021605. View

Azzouzi H, van Oort R, van der Nagel R, Sluiter W, Bergmann M, De Windt L . MEF2 transcriptional activity maintains mitochondrial adaptation in cardiac pressure overload. Eur J Heart Fail. 2009; 12(1):4-12. DOI: 10.1093/eurjhf/hfp165. View

Willems P, Rossignol R, Dieteren C, Murphy M, Koopman W . Redox Homeostasis and Mitochondrial Dynamics. Cell Metab. 2015; 22(2):207-18. DOI: 10.1016/j.cmet.2015.06.006. View

Chhabra R, Dubey R, Saini N . Cooperative and individualistic functions of the microRNAs in the miR-23a~27a~24-2 cluster and its implication in human diseases. Mol Cancer. 2010; 9:232. PMC: 2940846. DOI: 10.1186/1476-4598-9-232. View

Krzywinska E, Allende-Vega N, Cornillon A, Vo D, Cayrefourcq L, Panabieres C . Identification of Anti-tumor Cells Carrying Natural Killer (NK) Cell Antigens in Patients With Hematological Cancers. EBioMedicine. 2015; 2(10):1364-76. PMC: 4634619. DOI: 10.1016/j.ebiom.2015.08.021. View

10.

Gao P, Tchernyshyov I, Chang T, Lee Y, Kita K, Ochi T . c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature. 2009; 458(7239):762-5. PMC: 2729443. DOI: 10.1038/nature07823. View

11.

Kim M, Kim S, Lim J, Lee C, Choi H, Woo C . Laminar flow activation of ERK5 protein in vascular endothelium leads to atheroprotective effect via NF-E2-related factor 2 (Nrf2) activation. J Biol Chem. 2012; 287(48):40722-31. PMC: 3504785. DOI: 10.1074/jbc.M112.381509. View

12.

Hayes J, McMahon M . NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Trends Biochem Sci. 2009; 34(4):176-88. DOI: 10.1016/j.tibs.2008.12.008. View

13.

Jose C, Rossignol R . Rationale for mitochondria-targeting strategies in cancer bioenergetic therapies. Int J Biochem Cell Biol. 2012; 45(1):123-9. DOI: 10.1016/j.biocel.2012.07.005. View

14.

Villalba M, Rathore M, Lopez-Royuela N, Krzywinska E, Garaude J, Allende-Vega N . From tumor cell metabolism to tumor immune escape. Int J Biochem Cell Biol. 2012; 45(1):106-13. DOI: 10.1016/j.biocel.2012.04.024. View

15.

Eades G, Yang M, Yao Y, Zhang Y, Zhou Q . miR-200a regulates Nrf2 activation by targeting Keap1 mRNA in breast cancer cells. J Biol Chem. 2011; 286(47):40725-33. PMC: 3220489. DOI: 10.1074/jbc.M111.275495. View

16.

Jin P, Wang E, Ren J, Childs R, Shin J, Khuu H . Differentiation of two types of mobilized peripheral blood stem cells by microRNA and cDNA expression analysis. J Transl Med. 2008; 6:39. PMC: 2503968. DOI: 10.1186/1479-5876-6-39. View

17.

Abdul-Aziz A, MacEwan D, Bowles K, Rushworth S . Oxidative stress responses and NRF2 in human leukaemia. Oxid Med Cell Longev. 2015; 2015:454659. PMC: 4396545. DOI: 10.1155/2015/454659. View

18.

Kensler T, Wakabayashi N . Nrf2: friend or foe for chemoprevention?. Carcinogenesis. 2009; 31(1):90-9. PMC: 2802668. DOI: 10.1093/carcin/bgp231. View

19.

Bellance N, Lestienne P, Rossignol R . Mitochondria: from bioenergetics to the metabolic regulation of carcinogenesis. Front Biosci (Landmark Ed). 2009; 14(11):4015-34. DOI: 10.2741/3509. View

20.

Obre E, Rossignol R . Emerging concepts in bioenergetics and cancer research: metabolic flexibility, coupling, symbiosis, switch, oxidative tumors, metabolic remodeling, signaling and bioenergetic therapy. Int J Biochem Cell Biol. 2014; 59:167-81. DOI: 10.1016/j.biocel.2014.12.008. View