Silencing of elongation factor-2 kinase potentiates the effect of 2-deoxy-D-glucose against human glioma cells through blunting of autophagy.
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.
Wu
Hao
H
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.
Zhu
Hua
H
Liu
David X
DX
Niu
Ting-Kuang
TK
Ren
Xingcong
X
Patel
Rajesh
R
Hait
William N
WN
Yang
Jin-Ming
JM
D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000494:pharmacology*; D004357:Drug Synergism; D054736:Elongation Factor 2 Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection
D034741:RNA, Small Interfering; D003847:Deoxyglucose; D054736:Elongation Factor 2 Kinase