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Silencing of Elongation Factor-2 Kinase Potentiates the Effect of 2-Deoxy-D-Glucose against Human Glioma Cells through Blunting of Autophagy

Departments of Pharmacology, Neural and Behavioral Sciences, and The Penn State Cancer Institute, Pennsylvania State University College of Medicine and Milton S. Hershey Medical Center, Hershey, Pennsylvania

Requests for reprints: Jin-Ming Yang, Penn State College of Medicine, Department of Pharmacology, H072, 500 University Drive, P.O. Box 850, Hershey, PA 17033-0850. Phone: 717-531-0003, ext. 281124; Fax: 717-531-0002; E-mail: jyang2{at}hmc.psu.edu.

Key Words: elongation factor-2 kinase • 2-deoxy-D-glucose • glycolysis • autophagy • protein synthesis • glioblastoma

2-Deoxy-D-glucose (2-DG), a synthetic glucose analogue that acts as a glycolytic inhibitor, is currently being evaluated in the clinic as an anticancer agent. In this study, we observed that treatment of human glioma cells with 2-DG activated autophagy, a highly conserved cellular response to metabolic stress and a catabolic process of self-digestion of intracellular organelles for energy use and survival in stressed cells. The induction of autophagy by 2-DG was associated with activation of elongation factor-2 kinase (eEF-2 kinase), a structurally and functionally unique enzyme that phosphorylates eEF-2, leading to loss of affinity of this elongation factor for the ribosome and to termination of protein elongation. We also showed that inhibition of eEF-2 kinase by RNA interference blunted the 2-DG–induced autophagic response, resulted in a greater reduction of cellular ATP contents, and increased the sensitivity of tumor cells to the cytotoxic effect of 2-DG. Furthermore, the blunted autophagy and enhanced 2-DG cytotoxicity were accompanied by augmentation of apoptosis in cells in which eEF-2 kinase expression was knocked down. The results of this study indicate that the energy stress and cytotoxicity caused by 2-DG can be accelerated by inhibition of eEF-2 kinase, and suggest that targeting eEF-2 kinase–regulated autophagic survival pathway may represent a novel approach to sensitizing cancer cells to glycolytic inhibitors. [Cancer Res 2009;69(6):2453–60]