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Cancer Res. 2009 Mar 15;69(6):2453-60. doi: 10.1158/0008-5472.CAN-08-2872. Epub 2009 Feb 24.

Silencing of elongation factor-2 kinase potentiates the effect of 2-deoxy-D-glucose against human glioma cells through blunting of autophagy.

Author information

1
Department 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, USA.

Abstract

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.

PMID:
19244119
PMCID:
PMC2907516
DOI:
10.1158/0008-5472.CAN-08-2872
[Indexed for MEDLINE]
Free PMC Article

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