Targeting Energy Metabolic Pathways as Therapeutic Intervention for Breast Cancer

Abstract

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 observation 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 and tumor development and progression. Promotion of glycolysis by eEF-2K is mediated through the inhibitory effect of this kinase on translational elongation of protein phosphatase 2A-A (PP2A-A), a protein phosphatase that promotes the ubiquitin-proteasomal degradation of c-Myc. eEF-2K-mediated restriction of the synthesis of PP2A-A protein slows down the turnover of c-Myc, which activates the transcription of pyruvate kinase M2 isoform (PKM2), a key enzyme in the glycolytic pathway. 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. The results of this study not only provide the first connection between the regulation of protein synthesis and glycolysis activity, but also underscores the importance of eEF-2K in cancer, and the potential of this kinase as a novel target for prevention and treatment of this disease.