Loss of the respiratory enzyme citrate synthase directly links the Warburg effect to tumor malignancy

Sci Rep. 2012;2:785. doi: 10.1038/srep00785. Epub 2012 Nov 8.


To investigate whether altered energy metabolism induces the Warburg effect and results in tumor malignancy, the respiratory enzyme citrate synthase (CS) was examined, silenced, and the effects analyzed. In human cervical carcinoma cells, RNAi-mediated CS knockdown induced morphological changes characteristic of the epithelial-mesenchymal transition (EMT). This switch accelerated cancer cell metastasis and proliferation in in vitro assays and in vivo tumor xenograft models. Notably, CS knockdown cells exhibited severe defects in respiratory activity and marked decreases in ATP production, but great increases in glycolytic metabolism. This malignant progression was due to activation of EMT-related regulators; altered energy metabolism resulted from deregulation of the p53/TIGAR and SCO2 pathways. This phenotypic change was completely reversed by p53 reactivation via treatment with proteasome inhibitor MG132 or co-knockdown of E3 ligase HDM2 and partially suppressed by ATP treatment. This study directly links the Warburg effect to tumor malignancy via induction of the EMT phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / pharmacology
  • Animals
  • Apoptosis Regulatory Proteins
  • Carrier Proteins / metabolism
  • Cell Line, Tumor
  • Citrate (si)-Synthase / antagonists & inhibitors*
  • Citrate (si)-Synthase / genetics
  • Citrate (si)-Synthase / metabolism
  • Disease Progression
  • Energy Metabolism / drug effects
  • Epithelial-Mesenchymal Transition / drug effects
  • Female
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Leupeptins / pharmacology
  • Mice
  • Mice, Inbred NOD
  • Mitochondrial Proteins / metabolism
  • Phenotype
  • Proteasome Endopeptidase Complex / chemistry
  • Proteasome Endopeptidase Complex / metabolism
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Signal Transduction / drug effects
  • Transplantation, Heterologous
  • Tumor Suppressor Protein p53 / metabolism
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / pathology


  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Leupeptins
  • Mitochondrial Proteins
  • RNA, Small Interfering
  • SCO2 protein, human
  • Tumor Suppressor Protein p53
  • Adenosine Triphosphate
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Citrate (si)-Synthase
  • TIGAR protein, human
  • Proteasome Endopeptidase Complex
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde