The Nrf2 activator methyl bardoxolone exacerbates mitochondrial dysfunction in palmitate-treated breast cancer cells

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The mechanisms by which age and obesity are linked to breast cancer are not well understood. Saturated fatty acids are found at elevated circulating levels in ageing and obesity and can impact mitochondrial function. Recent studies have implicated mitochondrial dysregulation in obesity and breast cancer aetiology. As Nrf2 is a transcription factor that has been proposed as a target for both obesity and breast cancer, we have investigated whether saturated fatty acids can mediate altered mitochondrial function in the oestrogen-resistant MCF7 cell line and have studied the effect of Nrf2 activation. The major plasma saturated fatty acid, palmitate, increased the resting rate of glycolysis by 20% (extracellular acidification; Seahorse) in MCF7 cells; in contrast, at sub-lethal concentrations, palmitate marginally inhibited mitochondrial metabolism by 10% (not significant) when measured as oxygen consumption rate. Cell proliferation rate was inhibited significantly by palmitate. It is established that UCP1 and glutathione are both key to mitochondrial integrity and are regulated by Nrf2 in an opposing manner. As expected, methyl bardoxolone (BAR), an Nrf2 activator, increased the expression of GCLC mRNA and inhibited UCP1 expression associated with an increase in Mitosox oxidation. Paradoxically, the expression of mitochondrial UCP1 mRNA was inhibited more than 10 fold by palmitate but expression of the rate-limiting subunit in GSH synthesis GCLC was also inhibited by 50%. BAR prevented the loss of GCLC but not UCP1 mRNA and exacerbated mitochondrial dysfunction mediated by palmitate. Alone, BAR inhibited both glycolysis (P<0.001) and mitochondrial (P<0.001) function in the presence and absence of palmitate. Mitochondrial dysfunction due to BAR but not palmitate was prevented by N-acetyl cysteine suggesting that ROS are not the major drivers of metabolic switch or inhibitors of proliferation rate in the presence of the saturated fatty acid, palmitate.

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Original languageEnglish
PagesS32-S33
DOIs
Publication statusPublished - 1 Jul 2016

Employable Graduates; Exploitable Research

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