eEF-2 kinase is a critical regulator of Warburg effect through controlling PP2A-A synthesis
| Autor: | Yaxin Cheng, Yoshinori Takahashi, Guohui Wan, Harold A. Harvey, Shan Y, Jin Ming Yang, Jason Liao, David Liu, Xingcong Ren, Xi-Sha Chen, Yang Jw, Lan-ya Li, A. F. Chen, Li Zhang, Y. Yuan, Alexey G. Ryazanov, Gavin P. Robertson, Yongguang Tao, Li Y, Han B |
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| Rok vydání: | 2016 |
| Předmět: |
Elongation Factor 2 Kinase
0301 basic medicine Cancer Research Mice Nude Breast Neoplasms Biology Transfection medicine.disease_cause Mice 03 medical and health sciences Cell Line Tumor Genetics medicine Animals Humans Glycolysis Protein Phosphatase 2 Molecular Biology Kinase Protein phosphatase 2 Warburg effect Cell biology 030104 developmental biology Cancer cell MCF-7 Cells Heterografts Female Carcinogenesis Pyruvate kinase |
| Zdroj: | Oncogene. 35:6293-6308 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2016.166 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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