Abstract
Aerobic glycolysis (production of lactate from glucose in the presence of oxygen) is a hallmark of cancer. Fenofibrate is a lipid-lowering drug and an agonist of the peroxisome proliferator-activated receptor alpha (PPARα). We found that FF inhibited glycolysis in a PPARα-dependent manner in glioblastoma cells. Fenofibrate inhibited the transcriptional activity of NF-κB/RelA and also disrupted its association with hypoxia inducible factor1 alpha (HIF1α), which is required for the binding of NF-κB/RelA to the PKM promoter and PKM2 expression. High ratios of PKM2/PKM1 promote glycolysis and inhibit oxidative phosphorylation, thus favoring aerobic glycolysis. Fenofibrate decreased the PKM2/PKM1 ratio and caused mitochondrial damage. Given that fenofibrate is a widely used non-toxic drug, we suggest its use in patients with glioblastoma multiforme (GBM).
Keywords:
PKM2; PPARα; RelA; Warburg effect; fenofibrate.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Line, Tumor
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Female
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Fenofibrate / pharmacology*
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Glioblastoma / drug therapy*
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Glioblastoma / genetics
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Glioblastoma / metabolism
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Glycolysis / drug effects*
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Glycolysis / genetics
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice, Nude
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Microscopy, Electron, Transmission
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Mitochondria / drug effects
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Mitochondria / metabolism
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Mitochondria / ultrastructure
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NF-kappa B / genetics
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NF-kappa B / metabolism*
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PPAR alpha / genetics
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PPAR alpha / metabolism
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Thyroid Hormone-Binding Proteins
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Thyroid Hormones / genetics
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Thyroid Hormones / metabolism*
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Transcription Factor RelA / genetics
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Transcription Factor RelA / metabolism
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Transcriptional Activation / drug effects
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Tumor Burden / drug effects
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Tumor Burden / genetics
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Xenograft Model Antitumor Assays
Substances
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Carrier Proteins
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Membrane Proteins
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NF-kappa B
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PPAR alpha
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Thyroid Hormones
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Transcription Factor RelA
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Fenofibrate