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

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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 SCO 2 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.

Original languageEnglish
Article number785
JournalScientific reports
Volume2
DOIs
Publication statusPublished - 2012 Nov 22

All Science Journal Classification (ASJC) codes

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    Lin, C. C., Cheng, T. L., Tsai, W. H., Tsai, H. J., Hu, K. H., Chang, H. C., Yeh, C. W., Chen, Y. C., Liao, C. C., & Chang, W. T. (2012). Loss of the respiratory enzyme citrate synthase directly links the Warburg effect to tumor malignancy. Scientific reports, 2, [785]. https://doi.org/10.1038/srep00785