Abstract

Cancer cells predominantly metabolize glucose by glycolysis to produce energy in order to meet their metabolic requirement, a phenomenon known as Warburg effect. Although Warburg effect is considered a peculiarity critical for survival and proliferation of cancer cells, the regulatory mechanisms behind this phenomenon remain incompletely understood. We report here that eukaryotic elongation factor-2 kinase (eEF-2K), a negative regulator of protein synthesis, has a critical role in promoting glycolysis in cancer cells. We showed that deficiency in eEF-2K significantly reduced the uptake of glucose and decreased the productions of lactate and adenosine triphosphate in tumor cells and in the Ras-transformed mouse embryonic fibroblasts. We further demonstrated that the promotive effect of eEF-2K on glycolysis resulted from the kinase-mediated restriction of synthesis of the protein phosphatase 2A-A (PP2A-A), a key factor that facilitates the ubiquitin-proteasomal degradation of c-Myc protein, as knockdown of eEF-2K expression led to a significant increase in PP2A-A protein synthesis and remarkable downregulation of c-Myc and pyruvate kinase M2 isoform, the key glycolytic enzyme transcriptionally activated by c-Myc. In addition, depletion of eEF-2K reduced the ability of the transformed cells to proliferate and enhanced the sensitivity of tumor cells to chemotherapy both in vitro and in vivo. These results, which uncover a role of the eEF-2K-mediated control of PP2A-A in tumor cell glycolysis, provide new insights into the regulation of the Warburg effect.

Original languageEnglish (US)
Pages (from-to)6293-6308
Number of pages16
JournalOncogene
Volume35
Issue number49
DOIs
StatePublished - Dec 8 2016

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All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Cheng, Y., Ren, X., Yuan, Y., Shan, Y., Li, L., Chen, X., Zhang, L., Takahashi, Y., Yang, J. W., Han, B., Liao, J., Li, Y., Harvey, H., Ryazanov, A., Robertson, G. P., Wan, G., Liu, D., Chen, A. F., Tao, Y., & Yang, J. M. (2016). EEF-2 kinase is a critical regulator of Warburg effect through controlling PP2A-A synthesis. Oncogene, 35(49), 6293-6308. https://doi.org/10.1038/onc.2016.166