Suppression of mitochondrial respiration with auraptene inhibits the progression of renal cell carcinoma: involvement of HIF-1α degradation

Oncotarget. 2015 Nov 10;6(35):38127-38. doi: 10.18632/oncotarget.5511.


Renal cell carcinoma (RCC) progression resulting from the uncontrolled migration and enhanced angiogenesis is an obstacle to effective therapeutic intervention. Tumor metabolism has distinctive feature called Warburg effect, which enhances the aerobic glycolysis rapidly supplying the energy for migration of tumor. To manipulate this metabolic change characteristic of aggressive tumors, we utilized the citrus extract, auraptene, known as a mitochondrial inhibitor, testing its anticancer effects against the RCC4 cell line. We found that auraptene impaired RCC4 cell motility through reduction of mitochondrial respiration and glycolytic pathway-related genes. It also strongly disrupted VEGF-induced angiogenesis in vitro and in vivo. Hypoxia-inducible factor 1a (HIF-1a), a key regulator of cancer metabolism, migration and angiogenesis that is stably expressed in RCCs by virtue of a genetic mutation in the von Hippel-Lindau (VHL) tumor-suppressor protein, was impeded by auraptene, which blocked HIF-1a translation initiation without causing cytotoxicity. We suggest that blockade HIF-1a and reforming energy metabolism with auraptene is an effective approach for suspension RCC progression.

Keywords: HIF-1α; auraptene; eIF2α; mitochondrial respiration; renal cell carcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / pathology
  • Cell Movement / drug effects
  • Cell Respiration / drug effects
  • Coumarins / pharmacology*
  • Disease Progression
  • Dose-Response Relationship, Drug
  • Energy Metabolism / drug effects*
  • Gene Expression Regulation, Neoplastic
  • Glycolysis / drug effects
  • HeLa Cells
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / pathology
  • Male
  • Mice, Nude
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mutation
  • Neoplasm Invasiveness
  • Neovascularization, Physiologic / drug effects
  • Proteolysis
  • RNA Interference
  • Time Factors
  • Transfection
  • Tumor Burden / drug effects
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics
  • Xenograft Model Antitumor Assays


  • Angiogenesis Inhibitors
  • Coumarins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Von Hippel-Lindau Tumor Suppressor Protein
  • aurapten