Journal article
Inhibition of eEF-2 kinase sensitizes human glioma cells to TRAIL and down-regulates Bcl-xL expression
Biochemical and Biophysical Research Communications, Vol.414(1), pp.129-134
10/14/2011
DOI: 10.1016/j.bbrc.2011.09.038
PMCID: PMC3210449
PMID: 21945617
Abstract
► Inhibiting eEF-2 kinase sensitizes human glioma cells to TRAIL therapy. ► The enhanced sensitivity to TRAIL is accompanied by down-regulation of Bcl-xL. ► Overexpression of Bcl-xL can abrogate this sensitizing effect on TRAIL. ► Targeting eEF-2 kinase may represent a new adjuvant therapy with TRAIL. 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.
Details
- Title: Subtitle
- Inhibition of eEF-2 kinase sensitizes human glioma cells to TRAIL and down-regulates Bcl-xL expression
- Creators
- Yi Zhang - 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, USAYan Cheng - 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, USALi Zhang - Department of Pharmacology, School of Pharmacy, Soochow University, Jiangsu Province, ChinaXingcong Ren - 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, USAKathryn J Huber-Keener - 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, USASang Lee - 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, USAJong Yun - 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, USAHong-Gang Wang - 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, USAJin-Ming Yang - 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
- Resource Type
- Journal article
- Publication Details
- Biochemical and Biophysical Research Communications, Vol.414(1), pp.129-134
- DOI
- 10.1016/j.bbrc.2011.09.038
- PMID
- 21945617
- PMCID
- PMC3210449
- NLM abbreviation
- Biochem Biophys Res Commun
- ISSN
- 0006-291X
- eISSN
- 1090-2104
- Publisher
- Elsevier Inc
- Grant note
- name: US Public Health Service; DOI: 10.13039/501100001809, name: National Natural Sciences Foundation of China
- Language
- English
- Date published
- 10/14/2011
- Academic Unit
- Obstetrics and Gynecology
- Record Identifier
- 9983931288902771
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