Ethyl pyruvate stabilizes hypoxia-inducible factor 1 alpha via stimulation of the TCA cycle

Cancer Lett. 2010 Sep 28;295(2):236-41. doi: 10.1016/j.canlet.2010.03.006. Epub 2010 Mar 24.

Abstract

Ethyl pyruvate is a simple derivative of the endogenous metabolite pyruvate. Pyruvate is the starting substrate for the tricarboxylic acid (TCA) cycle and plays a central role in intermediary metabolism. The present study was to determine whether ethyl pyruvate affects the expression of hypoxia-inducible factor 1 alpha (HIF-1alpha) and to explore the mechanism of HIF-1alpha regulation. We found that ethyl pyruvate increased HIF-1alpha stability via inhibition of pVHL-mediated degradation. Furthermore, ethyl pyruvate enhanced the reactive oxygen species (ROS) generated through the TCA cycle in mitochondria. Taken together, our results support a novel role for ethyl pyruvate in HIF-1alpha stabilization by which high rates of the TCA cycle can promote ROS production.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Citric Acid Cycle / drug effects*
  • Hep G2 Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Mitochondria / metabolism
  • Pyruvates / pharmacology*
  • Reactive Oxygen Species / metabolism
  • Ubiquitination

Substances

  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Pyruvates
  • Reactive Oxygen Species
  • ethyl pyruvate