Journal article
Integrated regulation of autophagy and apoptosis by EEF2K controls cellular fate and modulates the efficacy of curcumin and velcade against tumor cells
Autophagy, Vol.9(2), pp.208-219
02/01/2013
DOI: 10.4161/auto.22801
PMCID: PMC3552884
PMID: 23182879
Abstract
Endoplasmic reticulum (ER) stress induces both autophagy and apoptosis yet the molecular mechanisms and pathways underlying the regulation of these two cellular processes in cells undergoing ER stress remain less clear. We report here that eukaryotic elongation factor-2 kinase (EEF2K) is a critical controller of the ER stress-induced autophagy and apoptosis in tumor cells. DDIT4, a stress-induced protein, was required for transducing the signal for activation of EEF2K under ER stress. We further showed that phosphorylation of EEF2K at Ser398 was essential for induction of autophagy, while phosphorylation of the kinase at Ser366 and Ser78 exerted an inhibitory effect on autophagy. Suppression of the ER stress-activated autophagy via silencing of EEF2K aggravated ER stress and promoted apoptotic cell death in tumor cells. Moreover, inhibiting EEF2K by either RNAi or NH125, a small molecule inhibitor of the enzyme, rendered tumor cells more sensitive to curcumin and velcade, two anticancer agents that possess ER stress-inducing action. Our study indicated that the DDIT4-EEF2K pathway was essential for inducing autophagy and for determining the fate of tumor cells under ER stress, and suggested that inhibiting the EEF2K-mediated autophagy can deteriorate ER stress and lead to a greater apoptotic response, thereby potentiating the efficacy of the ER stress-inducing agents against cancer.
Details
- Title: Subtitle
- Integrated regulation of autophagy and apoptosis by EEF2K controls cellular fate and modulates the efficacy of curcumin and velcade against tumor cells
- Creators
- Yan Cheng - Penn State Milton S. Hershey Medical CenterXingcong Ren - Penn State Milton S. Hershey Medical CenterYi Zhang - Penn State Milton S. Hershey Medical CenterYu Shan - Penn State Milton S. Hershey Medical CenterKathryn J. Huber-Keener - Penn State Milton S. Hershey Medical CenterLi Zhang - Penn State Milton S. Hershey Medical CenterScot R. Kimball - Penn State Milton S. Hershey Medical CenterHarold Harvey - Penn State Milton S. Hershey Medical CenterLeonard S. Jefferson - Penn State Milton S. Hershey Medical CenterJin-Ming Yang - Penn State Univ, Dept Pharmacol, Penn State Hershey Canc Inst, Coll Med, Hershey, PA USA
- Resource Type
- Journal article
- Publication Details
- Autophagy, Vol.9(2), pp.208-219
- DOI
- 10.4161/auto.22801
- PMID
- 23182879
- PMCID
- PMC3552884
- NLM abbreviation
- Autophagy
- ISSN
- 1554-8627
- eISSN
- 1554-8635
- Publisher
- Landes Bioscience
- Number of pages
- 12
- Grant note
- 81072146 / National Natural Sciences Foundation of China; National Natural Science Foundation of China (NSFC) BC103654 / Department of Defense; United States Department of Defense Elsa Pardee Foundation R01CA135038; R01DK13499 / US. Public Health Service; United States Department of Health & Human Services; United States Public Health Service R01DK013499 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) R01CA135038 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 02/01/2013
- Academic Unit
- Obstetrics and Gynecology
- Record Identifier
- 9984318325302771
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