Aberrant IDH3α expression promotes malignant tumor growth by inducing HIF-1-mediated metabolic reprogramming and angiogenesis

Oncogene. 2015 Sep 3;34(36):4758-66. doi: 10.1038/onc.2014.411. Epub 2014 Dec 22.

Abstract

Cancer cells gain a growth advantage through the so-called Warburg effect by shifting glucose metabolism from oxidative phosphorylation to aerobic glycolysis. Hypoxia-inducible factor 1 (HIF-1) has been suggested to function in metabolic reprogramming; however, the underlying mechanism has not been fully elucidated. We found that the aberrant expression of wild-type isocitrate dehydrogenase 3α (IDH3α), a subunit of the IDH3 heterotetramer, decreased α-ketoglutarate levels and increased the stability and transactivation activity of HIF-1α in cancer cells. The silencing of IDH3α significantly delayed tumor growth by suppressing the HIF-1-mediated Warburg effect and angiogenesis. IDH3α expression was associated with the poor postoperative overall survival of lung and breast cancer patients. These results justify the exploitation of IDH3 as a novel target for the diagnosis and treatment of cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Glucose / metabolism
  • Glycolysis
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Isocitrate Dehydrogenase / antagonists & inhibitors
  • Isocitrate Dehydrogenase / biosynthesis*
  • Isocitrate Dehydrogenase / genetics
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Mice
  • Neovascularization, Pathologic / genetics*
  • Neovascularization, Pathologic / pathology
  • Oxidative Phosphorylation

Substances

  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Isocitrate Dehydrogenase
  • Glucose