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eEF-2 kinase is a critical regulator of Warburg effect through controlling PP2A-A synthesis

Oncogene volume 35, pages 6293–6308 (2016)Cite this article

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A Correction to this article was published on 04 July 2018

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.

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Acknowledgements

We sincerely thank Dr Zhimin Lu (MD Anderson Cancer Center, USA) and Drs Jing Chen and Taro Hitosugi (Emory University School of Medicine) for PKM2 plasmids, Dr Christopher Proud (University of Southampton, UK) for eEF-2K plasmid and Dr Jayanta Debnath (University of California San Francisco, USA) for H-RasV12 retroviral plasmid. This work was supported by grants from the National Basic Research Program of China (973 Program) 2015CB910700 (to YC), 2014CB542400 (to AFC); the National Natural Science Foundation of China 81422051, 81472593 and 31401208 (to YC); the National Basic Research Program of China 2015CB553903 (to YT) and the National Natural Science Foundation of China 81372427 (to YT); the US Department of Defense BC103654 (to YC); and the US Public Health Service NIH/NCI R01CA135038 (to J-MY).

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Authors and Affiliations

  1. Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, China

    Y Cheng, L Li & X Chen

  2. Department of Pharmacology, The Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine and Milton S Hershey Medical Center, Hershey, PA, USA

    Y Cheng, X Ren, Y Shan, L Zhang, Y Takahashi, J W Yang, Y Li, G P Robertson, G Wan & J-M Yang

  3. Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, WA, USA

    Y Yuan & D Liu

  4. Department of Pathology, The Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine and Milton S Hershey Medical Center, Hershey, PA, USA

    B Han

  5. Division of Biostatistics and Bioinformatics, The Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine and Milton S Hershey Medical Center, Hershey, PA, USA

    J Liao

  6. Department of Medicine, The Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine and Milton S Hershey Medical Center, Hershey, PA, USA

    H Harvey

  7. Department of Pharmacology, Robert wood Jonson Medical School, Rutgers University, Piscataway, NJ, USA

    A Ryazanov

  8. Center for Vascular and Translational Medicine, College of Pharmacy, and The Third Xiangya Hospital, Central South University, Changsha, Hunan, China

    A F Chen

  9. Cancer Research Institute, School of Basic Medicine, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Central South University, Changsha, China

    Y Tao

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Cheng, Y., Ren, X., Yuan, Y. et al. eEF-2 kinase is a critical regulator of Warburg effect through controlling PP2A-A synthesis. Oncogene 35, 6293–6308 (2016). https://doi.org/10.1038/onc.2016.166

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