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Bardoxolone-methyl inhibits migration and metabolism in MCF7 cells
Alaa Refaat1,2,3, Chathyan Pararasa1, Muhammed Arif1
1a Life & Health Sciences , Aston University , Birmingham , UK.
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.
Insights
Bardoxolone-methyl (BAR) inhibits breast cancer cell migration and proliferation by impacting mitochondrial function and increasing reactive oxygen species (ROS). Nrf2 activation by BAR plays a key role in these anti-cancer effects.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Bardoxolone-methyl (BAR) exhibits anti-inflammatory, anti-proliferative, and anti-fibrotic properties by activating Nrf2 and potentially reducing oxidative stress.
- Off-target effects of BAR, possibly linked to concentration and NFkB signaling, have restricted its clinical applications.
- Nrf2 is a regulator of antioxidant and mitochondrial genes, making it a potential therapeutic target for obesity and breast cancer.
Purpose of the Study:
- To investigate the effects of Bardoxolone-methyl (BAR) on MCF7 breast cancer cell migration, proliferation, and metabolic function.
- To explore the role of Nrf2 activation and reactive oxygen species (ROS) in BAR's effects on MCF7 cells.
- To examine the influence of fatty acids, such as palmitate, on BAR's efficacy and cellular response.
Main Methods:
- MCF7 cells were treated with BAR, and effects on migration, proliferation, mitochondrial respiration, and ROS production were assessed.
- Gene expression of Nrf2 targets (GCLC, UCP1) and signaling pathways (AKT, NFkB) were analyzed.
- Metabolic assays including glycolytic capacity and oxidative phosphorylation were performed.
- The role of N-acetyl cysteine and proteasome inhibition in modulating BAR's effects were investigated.
Main Results:
- BAR treatment inhibited MCF7 cell migration and decreased mitochondrial respiration in a time-dependent manner.
- BAR reduced glycolytic capacity and oxidative phosphorylation, increased mitochondrial ROS, and depleted glutathione, effects partially mitigated by N-acetyl cysteine.
- BAR activated AKT, induced DNA damage, and inhibited cell proliferation.
- Fatty acid palmitate exacerbated mitochondrial ROS and impaired migration and oxidative phosphorylation, with distinct mechanisms from BAR.
- Evidence suggested non-canonical NFkB signaling involvement in BAR's effects.
Conclusions:
- BAR-induced ROS are critical mediators of inhibited MCF7 cell migration and metabolism, impacting glycolytic capacity and mitochondrial function.
- BAR demonstrates potential as an anti-cancer agent by targeting Nrf2 and disrupting cellular metabolism and proliferation in breast cancer cells.
- Understanding BAR's complex interactions with cellular pathways, including NFkB and fatty acid metabolism, is crucial for optimizing its therapeutic use.
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