Bardoxolone-methyl inhibits migration and metabolism in MCF7 cells

Alaa Refaat, Chathyan Pararasa, Muhammad Arif, James E.P. Brown, Amtul Carmichael, Sameh S. Ali, Hiroaki Sakurai, Helen R. Griffiths

Research output: Contribution to journalArticle

Abstract

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.

LanguageEnglish
Pages211-221
Number of pages11
JournalFree Radical Research
Volume51
Issue number2
Early online date14 Feb 2017
DOIs
Publication statusPublished - 2017

Fingerprint

MCF-7 Cells
Metabolism
Acetylcysteine
Palmitates
Oxidative Phosphorylation
Cysteine
methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate
Fatty Acids
Antioxidants
Genes
Phosphorylation
Oxidative stress
Mitochondrial Genes
Cell proliferation
Proteasome Endopeptidase Complex
DNA Damage
Glutathione
Toxicity
Respiration
Oxidative Stress

Bibliographical note

This is an Accepted Manuscript of an article published by Taylor & Francis in Free Radical Research on 14/2/17, available online: http://www.tandfonline.com/10.1080/10715762.2017.1295452

Keywords

  • breast cancer
  • glutathione
  • glycolysis
  • mitochondria
  • palmitate
  • reactive oxygen species

Cite this

Refaat, A., Pararasa, C., Arif, M., Brown, J. E. P., Carmichael, A., Ali, S. S., ... Griffiths, H. R. (2017). Bardoxolone-methyl inhibits migration and metabolism in MCF7 cells. Free Radical Research, 51(2), 211-221. https://doi.org/10.1080/10715762.2017.1295452
Refaat, Alaa ; Pararasa, Chathyan ; Arif, Muhammad ; Brown, James E.P. ; Carmichael, Amtul ; Ali, Sameh S. ; Sakurai, Hiroaki ; Griffiths, Helen R. / Bardoxolone-methyl inhibits migration and metabolism in MCF7 cells. In: Free Radical Research. 2017 ; Vol. 51, No. 2. pp. 211-221.
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Refaat, A, Pararasa, C, Arif, M, Brown, JEP, Carmichael, A, Ali, SS, Sakurai, H & Griffiths, HR 2017, 'Bardoxolone-methyl inhibits migration and metabolism in MCF7 cells' Free Radical Research, vol. 51, no. 2, pp. 211-221. https://doi.org/10.1080/10715762.2017.1295452

Bardoxolone-methyl inhibits migration and metabolism in MCF7 cells. / Refaat, Alaa; Pararasa, Chathyan; Arif, Muhammad; Brown, James E.P.; Carmichael, Amtul; Ali, Sameh S.; Sakurai, Hiroaki; Griffiths, Helen R.

In: Free Radical Research, Vol. 51, No. 2, 2017, p. 211-221.

Research output: Contribution to journalArticle

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T1 - Bardoxolone-methyl inhibits migration and metabolism in MCF7 cells

AU - Refaat, Alaa

AU - Pararasa, Chathyan

AU - Arif, Muhammad

AU - Brown, James E.P.

AU - Carmichael, Amtul

AU - Ali, Sameh S.

AU - Sakurai, Hiroaki

AU - Griffiths, Helen R.

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