Bardoxolone-methyl inhibits migration and metabolism in MCF7 cells


Bardoxolone-methyl (BAR) is reported to have anti-inflammatory, anti-proliferative and anti-fibrotic effects. BAR activates Nrf2 and may ameliorate oxidative stress through induction of antioxidant genes. However, off-target effects, probably concentration and NFkB-dependent, have limited the clinical use of BAR. Nrf2 regulates expression of antioxidant and mitochondrial genes and has been proposed as a target for both obesity and breast cancer. Therefore, we explored whether BAR can alter migration and proliferation in the MCF7 cell line and whether metabolic function is affected by BAR. Incubation with BAR caused a time-dependent migratory inhibition and an associated decrease in mitochondrial respiration. Both migratory and mitochondrial inhibition by BAR were further enhanced in the presence of fatty acids. In addition to the activation of Nrf2, BAR altered the expression of target mRNA GCLC and UCP1. After 24 h, BAR inhibited both glycolytic capacity, reserve (p < 0.05) and oxidative phosphorylation (p < 0.001) with an associated increase in mitochondrial ROS and loss of intracellular glutathione in MCF7 cells; however, impairment of mitochondrial activity was prevented by N-acetyl cysteine. The fatty acid, palmitate, increased mitochondrial ROS, impaired migration and oxidative phosphorylation but palmitate toxicity towards MCF7 could not be inhibited by N-acetyl cysteine suggesting that they exert effects through different pathways. BAR-activated AKT, induced DNA damage and inhibited cell proliferation. When the proteasome was inhibited, there was loss of BAR-mediated changes in p65 phosphorylation and SOD2 expression suggesting non-canonical NFkB signaling effects. These data suggest that BAR-induced ROS are important in inhibiting MCF7 migration and metabolism by negatively affecting glycolytic capacity and mitochondrial function.

Publication DOI:
Divisions: College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences > Chronic and Communicable Conditions
College of Health & Life Sciences
College of Health & Life Sciences > School of Biosciences > Cell & Tissue Biomedical Research
Additional Information: This is an Accepted Manuscript of an article published by Taylor & Francis in Free Radical Research on 14/2/17, available online:
Uncontrolled Keywords: breast cancer,glutathione,glycolysis,mitochondria,palmitate,reactive oxygen species,Biochemistry
Publication ISSN: 1029-2470
Last Modified: 27 May 2024 07:18
Date Deposited: 04 Apr 2017 08:10
Full Text Link:
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2017-03-13
Published Online Date: 2017-02-14
Accepted Date: 2017-02-11
Submitted Date: 2016-11-10
Authors: Refaat, Alaa
Pararasa, Chathyan
Arif, Muhammad
Brown, James E.P. (ORCID Profile 0000-0002-3504-7373)
Carmichael, Amtul
Ali, Sameh S.
Sakurai, Hiroaki
Griffiths, Helen R. (ORCID Profile 0000-0002-2666-2147)



Version: Accepted Version

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