Eukaryotic elongation factor 2 kinase confers tolerance to stress conditions in cancer cells

Zhu, Hongcheng; Yang, Xi; Liu, Jia; Zhou, Lu; Zhang, Chi; Xu, Liping; Qin, Qin; Li, Zhan; Lü, Jing; Cheng, Hongyan; Sun, Xinchen

doi:10.1007/s12192-014-0545-0

Cited by 32 publications

(22 citation statements)

References 28 publications

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“…4C). Eukaryotic elongation factor-2 kinase (eEF2K) has been reported to contribute to carcinogenesis [15][16]. Intriguingly, western blot analysis showed that the protein expression of eEF2K in the GAPLINC silencing group decreased significantly compared with the control group (Fig.…”

Section: Lncrna Gaplinc Silencing Inhibits the Tumor Growth Of Nsclc mentioning

confidence: 92%

Gastric Adenocarcinoma Predictive Long Intergenic Non-Coding RNA Promotes Tumor Occurrence and Progression in Non-Small Cell Lung Cancer via Regulation of the miR-661/eEF2K Signaling Pathway

Gu¹,

Chen²,

Song³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Long non-coding RNAs (lncRNAs) play vital roles in carcinogenesis as oncogenes or tumor suppressor genes. This study explored the biological function of lncRNA gastric adenocarcinoma predictive long intergenic non-coding RNA (GAPLINC) in human non-small cell lung cancer (NSCLC). Methods: GAPLINC expression in NSCLC specimens and cell lines was detected by qRT-PCR and Western blot. The effect of GAPLINC on cell proliferation was investigated using CCK8-assay, colony formation assay, and xenograft model. The effects of GAPLINC on apoptosis and cell cycle were determined using flow cytometry. The mechanism of GAPLINC involved in NSCLC was explored using Western blot, luciferase reporter assay, and RNA fluorescence in situ hybridization. Results: We found that GAPLINC expression was up-regulated in NSCLC tissues and cell lines. Overexpression of GAPLINC was associated with poor prognosis in patients with NSCLC. Silencing of GAPLINC significantly inhibited cell proliferation, promoted apoptosis, and induced cell cycle arrest in the G0/G1 phase. Results from xenograft transplantation showed that GAPLINC silencing inhibited the tumor growth in vivo. Interestingly, GAPLINC silencing decreased the expression of eukaryotic elongation factor-2 kinase (eEF2K) protein both in vivo and in vitro. Bioinformatic analysis and luciferase reporter confirmed that miR-661 targeted GAPLINC and eEF2K 3’-UTR and was negatively correlated with the expression of GAPLINC and eEF2K. Conclusion: Our findings indicate that GAPLINC promotes NSCLC tumorigenesis by regulating miR-661/eEF2K cascade and provide new insights for the pathogenesis underlying NSCLC and potential targets for therapeutic strategy.

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Section: Lncrna Gaplinc Silencing Inhibits the Tumor Growth Of Nsclc mentioning

confidence: 92%

Gastric Adenocarcinoma Predictive Long Intergenic Non-Coding RNA Promotes Tumor Occurrence and Progression in Non-Small Cell Lung Cancer via Regulation of the miR-661/eEF2K Signaling Pathway

Gu¹,

Chen²,

Song³

et al. 2018

Cell Physiol Biochem

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“…eEF2K-induced phosphorylation of eEF2 changes it into an inactive state, which, in turn, inhibits the protein translation. Expression and activation of eEF2K increase in tumor tissues from the pancreas and breasts, where eEF2K facilitates the proliferation and viability of tumor cells through positively modulating the cell cycle and autophagy (30). Thus, it has been proposed that eEF2K affects the pathogenesis of other cell proliferation-associated diseases than cancer.…”

mentioning

confidence: 99%

Eukaryotic elongation factor 2 kinase mediates monocrotaline-induced pulmonary arterial hypertension via reactive oxygen species-dependent vascular remodeling

Kameshima

Kazama

Okada

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Pulmonary arterial (PA) hypertension (PAH) is a progressive and lethal disease that is caused by increased vascular contractile reactivity and structural remodeling. These changes contribute to increasing pulmonary peripheral vascular resistance, finally leading to right heart failure and death. Eukaryotic elongation factor 2 kinase (eEF2K) is a Ca(2+)/calmodulin-dependent protein kinase. We previously revealed that eEF2K protein increases in the mesenteric artery from spontaneously hypertensive rats and partly mediates the development of hypertension via a promotion of ROS-dependent vascular inflammatory responses and proliferation and migration of vascular smooth muscle cells. However, a role of eEF2K in the pathogenesis of PAH is unknown. In the present study, we tested the hypothesis that eEF2K may be involved in the pathogenesis of PAH. PAH was induced by a single intraperitoneal injection of monocrotaline (MCT; 60 mg/kg) to rats. A specific eEF2K inhibitor, A-484954 (2.5 mg·kg(-1)·day(-1)), was intraperitoneally injected for 14 days. Long-term A-484954 treatment inhibited MCT-induced increased PA pressure. It was revealed that A-484954 inhibited MCT-induced PA hypertrophy and fibrosis but not impairment of endothelium-dependent and -independent relaxation. Furthermore, A-484954 inhibited MCT-induced NADPH oxidase-1 expression and ROS generation as well as matrix metalloproteinase-2 activation. In conclusion, the present results suggest that eEF2K at least partly mediates MCT-induced PAH via stimulation of vascular structural remodeling perhaps through NADPH oxidase-1/ROS/matrix metalloproteinase-2 pathway.

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“…eEF2K is inactivated by phosphorylation at Ser359. eEF2K has been shown to also be upregulated in cancer (48,53,73,75). One study of particular interest looked at eEF2K in transformed cells under acute verses chronic nutrient deprivation (46).…”

Section: Discussionmentioning

confidence: 99%

Intrauterine growth restriction inhibits expression of eukaryotic elongation factor 2 kinase, a regulator of protein translation

McKnight

Yost

Zinkhan

et al. 2016

Physiological Genomics

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Nutrient deprivation suppresses protein synthesis by blocking peptide elongation. Transcriptional upregulation and activation of eukaryotic elongation factor 2 kinase (eEF2K) blocks peptide elongation by phosphorylating eukaryotic elongation factor 2. Previous studies examining placentas from intrauterine growth restricted (IUGR) newborn infants show decreased eEF2K expression and activity despite chronic nutrient deprivation. However, the effect of IUGR on hepatic eEF2K expression in the fetus is unknown. We, therefore, examined the transcriptional regulation of hepatic eEF2K gene expression in a Sprague-Dawley rat model of IUGR. We found decreased hepatic eEF2K mRNA and protein levels in IUGR offspring at birth compared with control, consistent with previous placental observations. Furthermore, the CpG island within the eEF2K promoter demonstrated increased methylation at a critical USF 1/2 transcription factor binding site. In vitro methylation of this binding site caused near complete loss of eEF2K promoter activity, designating this promoter as methylation sensitive. The eEF2K promotor in IUGR offspring also lost the protective histone covalent modifications associated with unmethylated CGIs. In addition, the +1 nucleosome was displaced 3' and RNA polymerase loading was reduced at the IUGR eEF2K promoter. Our findings provide evidence to explain why IUGR-induced chronic nutrient deprivation does not result in the upregulation of eEF2K gene transcription.

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Eukaryotic elongation factor 2 kinase confers tolerance to stress conditions in cancer cells

Cited by 32 publications

References 28 publications

Gastric Adenocarcinoma Predictive Long Intergenic Non-Coding RNA Promotes Tumor Occurrence and Progression in Non-Small Cell Lung Cancer via Regulation of the miR-661/eEF2K Signaling Pathway

Gastric Adenocarcinoma Predictive Long Intergenic Non-Coding RNA Promotes Tumor Occurrence and Progression in Non-Small Cell Lung Cancer via Regulation of the miR-661/eEF2K Signaling Pathway

Eukaryotic elongation factor 2 kinase mediates monocrotaline-induced pulmonary arterial hypertension via reactive oxygen species-dependent vascular remodeling

Intrauterine growth restriction inhibits expression of eukaryotic elongation factor 2 kinase, a regulator of protein translation

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