title: Inhibition of eEF-2 kinase sensitizes human glioma cells to TRAIL and down-regulates Bcl-xL expression.
abstract: Elongation factor-2 kinase (eEF-2 kinase, also known as calmodulin-dependent protein kinase III), is a unique calcium/calmodulin-dependent enzyme that inhibits protein synthesis by phosphorylating and inactivating elongation factor-2 (eEF-2). We previously reported that expression/activity of eEF-2 kinase was up-regulated in several types of malignancies including Gliomas, and was associated with response of tumor cells to certain therapeutic stress. In the current study, we sought to determine whether eEF-2 kinase expression affected sensitivity of glioma cells to treatment with tumor the necrosis factor-related apoptosis-inducing ligand (TRAIL), a targeted therapy able to induce apoptosis in cancer cells but causes no toxicity in most normal cells. We found that inhibition of eEF-2 kinase by RNA interference (RNAi) or by a pharmacological inhibitor (NH125) enhanced TRAIL-induced apoptosis in the human glioma cells, as evidenced by an increase in apoptosis in the tumor cells treated with eEF-2 kinase siRNA or the eEF-2 kinase inhibitor. We further demonstrated that sensitization of tumor cells to TRAIL was accompanied by a down-regulation of the anti-apoptotic protein, Bcl-xL, and that overexpression of Bcl-xL could abrogate the sensitizing effect of inhibiting eEF-2 kinase on TRAIL. The results of this study may help devise a new therapeutic strategy for enhancing the efficacy of TRAIL against malignant glioma by targeting eEF-2 kinase.
authors.affiliation: Department of Pharmacology and The Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine and Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA. zhangyi@suda.edu.cn
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Cheng
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Xingcong
authors.initials: X
authors.lastname: Ren
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Huber-Keener
authors.forename: Sang
authors.initials: S
authors.lastname: Lee
authors.forename: Jong
authors.initials: J
authors.lastname: Yun
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Wang
authors.forename: Jin-Ming
authors.initials: JM
authors.lastname: Yang
mesh_terms: D001932:Brain Neoplasms / Q000201:enzymology*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D054736:Elongation Factor 2 Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics; D018390:Gene Targeting; D005910:Glioma / Q000201:enzymology*; D006801:Humans; D034622:RNA Interference; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: C494811:BCL2L1 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; D051020:bcl-X Protein; C517689:EEF2K protein, human; D054736:Elongation Factor 2 Kinase