title: eEF-2 kinase is a critical regulator of Warburg effect through controlling PP2A-A synthesis.
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.
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, China.|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.
authors.forename: Y
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: 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.
authors.forename: X
authors.initials: X
authors.lastname: Ren
authors.affiliation: Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, WA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: 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.
authors.forename: Y
authors.initials: Y
authors.lastname: Shan
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, China.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, China.
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Y
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: 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.
authors.forename: J W
authors.initials: JW
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: B
authors.initials: B
authors.lastname: Han
authors.affiliation: 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.
authors.forename: J
authors.initials: J
authors.lastname: Liao
authors.affiliation: 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.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: 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.
authors.forename: H
authors.initials: H
authors.lastname: Harvey
authors.affiliation: Department of Pharmacology, Robert wood Jonson Medical School, Rutgers University, Piscataway, NJ, USA.
authors.forename: A
authors.initials: A
authors.lastname: Ryazanov
authors.affiliation: 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.
authors.forename: G P
authors.initials: GP
authors.lastname: Robertson
authors.affiliation: 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.
authors.forename: G
authors.initials: G
authors.lastname: Wan
authors.affiliation: Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, WA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Liu
authors.affiliation: Center for Vascular and Translational Medicine, College of Pharmacy, and The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: A F
authors.initials: AF
authors.lastname: Chen
authors.affiliation: Cancer Research Institute, School of Basic Medicine, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Central South University, Changsha, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Tao
authors.affiliation: 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.
authors.forename: J-M
authors.initials: JM
authors.lastname: Yang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics; D045744:Cell Line, Tumor; D054736:Elongation Factor 2 Kinase / Q000235:genetics / Q000378:metabolism*; D005260:Female; D064593:Heterografts; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D054648:Protein Phosphatase 2 / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection
chemical_list: C517689:EEF2K protein, human; D054736:Elongation Factor 2 Kinase; D054648:Protein Phosphatase 2