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

Hao Wu, Hua Zhu, David X. Liu, Ting Kuang Niu, Xingcong Ren, Rajesh Patel, William N. Hait, Jin Ming Yang

Research output: Contribution to journalArticle

75 Scopus citations

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 UNA 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.

Original languageEnglish (US)
Pages (from-to)2453-2460
Number of pages8
JournalCancer Research
Volume69
Issue number6
DOIs
StatePublished - Mar 15 2009

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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