NF-κB/RelA-PKM2 mediates inhibition of glycolysis by fenofibrate in glioblastoma cells

Oncotarget. 2015 Sep 22;6(28):26119-28. doi: 10.18632/oncotarget.4444.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Female
  • Fenofibrate / pharmacology*
  • Glioblastoma / drug therapy*
  • Glioblastoma / genetics
  • Glioblastoma / metabolism
  • Glycolysis / drug effects*
  • Glycolysis / genetics
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice, Nude
  • Microscopy, Electron, Transmission
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondria / ultrastructure
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • PPAR alpha / genetics
  • PPAR alpha / metabolism
  • Thyroid Hormone-Binding Proteins
  • Thyroid Hormones / genetics
  • Thyroid Hormones / metabolism*
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism
  • Transcriptional Activation / drug effects
  • Tumor Burden / drug effects
  • Tumor Burden / genetics
  • Xenograft Model Antitumor Assays

Substances

  • Carrier Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Membrane Proteins
  • NF-kappa B
  • PPAR alpha
  • Thyroid Hormones
  • Transcription Factor RelA
  • Fenofibrate