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

• Published in: Scientific reports Vol. 2; no. 1; p. 785
• Main Authors: Lin, Chin-Chih, Cheng, Tsung-Lin, Tsai, Wen-Hui, Tsai, Hui-Ju, Hu, Keng-Hsun, Chang, Hao-Chun, Yeh, Chin-Wei, Chen, Ying-Chou, Liao, Ching-Chun, Chang, Wen-Tsan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.11.2012; Nature Publishing Group
• Subjects: 631/208/191/505; 631/45/320; 631/67/70; 631/80/641/83; Adenosine Triphosphate - pharmacology; Animals; Apoptosis Regulatory Proteins; Carrier Proteins - metabolism; Cell Line, Tumor; Cervical cancer; Citrate (si)-Synthase - antagonists & inhibitors; Citrate (si)-Synthase - genetics; Citrate (si)-Synthase - metabolism; Deregulation; Disease Progression; Energy Metabolism - drug effects; Enzymes; Epithelial-Mesenchymal Transition - drug effects; Female; HeLa Cells; Humanities and Social Sciences; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Leupeptins - pharmacology; Metabolism; Mice; Mice, Inbred NOD; Mitochondrial Proteins - metabolism; multidisciplinary; p53 Protein; Phenotype; Physical characteristics; Proteasome Endopeptidase Complex - chemistry; Proteasome Endopeptidase Complex - metabolism; Proteasomes; 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; Science; Signal transduction; Signal Transduction - drug effects; Transplantation, Heterologous; Tumor Suppressor Protein p53 - metabolism; Tumors; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - pathology; Xenografts
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep00785

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.