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

Chin-Chih Lin; Tsung-Lin Cheng; Wen-Hui Tsai; Hui-Ju Tsai; Keng-Hsun Hu; Hao-Chun Chang; Chin-Wei Yeh; Ying-Chou Chen; Ching-Chun Liao; Wen-Tsan Chang

doi:10.1038/srep00785

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.

Authors

Chin-Chih Lin¹, Tsung-Lin Cheng, Wen-Hui Tsai, Hui-Ju Tsai, Keng-Hsun Hu, Hao-Chun Chang, Chin-Wei Yeh, Ying-Chou Chen, Ching-Chun Liao, Wen-Tsan Chang

Affiliation

¹ Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan 701, Taiwan, ROC.

Abstract

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
Molecular Chaperones
Phenotype
Phosphoric Monoester Hydrolases
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

Substances

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