1-Benzyl-3-cetyl-2-methylimidazolium iodide (NH125) Induces Phosphorylation of Eukaryotic Elongation Factor-2 (eEF2)

Chen, Zehan; Gopalakrishnan, Sujatha M.; Bui, Mai-Ha; Soni, Nirupama B.; Warrior, Usha; Johnson, Eric F.; Donnelly, Jennifer; Glaser, Keith B.

doi:10.1074/jbc.m111.301291

Cited by 100 publications

(144 citation statements)

References 30 publications

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“…Arora et al found that NH125 inhibited the eEF2K activity and blocked the phosphorylation of eEF2 in the glioma cell lines as a potential anticancer drug [23]. Interestingly, Chen et al indicated that NH125 inhibited the growth of H1299 cells through inhibiting the expression of eEF2K and inducing the phosphorylation of eEF2, which were different from most of other studies and what we have found [24]. Further studies are needed to further characterize the radiosensitive mechanisms of NH125 in breast cancer.…”

Section: Discussioncontrasting

confidence: 55%

NH125, an eukaryotic elongation factor 2 kinase inhibitor, radiosensitizes breast cancer by the abrogation of G2/M checkpoint

Song¹,

Chen²,

Zhu³

et al. 2017

J Cancer Ther Res

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Radiotherapy remains an important treatment option for both surgical and non-surgical breast cancer patients; however resistance to radiation results in tumor recurrence and metastasis. eEF2K has been reported to play a critical role in cancer development and progression, but little is related to its radiosensitization effect. This study aimed to evaluate the radiosensitization effect of NH125, an eukaryotic elongation factor 2 kinase inhibitor, in breast cancer MDA-MB-231 and MCF-7. Cell proliferation rate was evaluated by Cell Counting Kit 8 assay. Cell cycle distribution and apoptosis rate were detected by flow cytometry. Radiosensitization ratio was evaluated by clonogenic survival assay. DNA damage repair was detected by immunofluorescent assay. Tumor-bearing xenografts confirmed the radiosensitization effect in vivo. NH125 potently sensitized MDA-MB-231 and MCF-7 to radiation with sensitization enhancement ratios 1.29 and 1.43 respectively. NH125 enhanced the radiosensitization through abrogation of G2 checkpoint and prolongation of DNA damage repair. Above all, these results demonstrated that NH125 may be a promising radiosensitizer in breast cancer radiotherapy.

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Section: Discussioncontrasting

confidence: 55%

NH125, an eukaryotic elongation factor 2 kinase inhibitor, radiosensitizes breast cancer by the abrogation of G2/M checkpoint

Song¹,

Chen²,

Zhu³

et al. 2017

J Cancer Ther Res

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“…A thiopyran-dicarbonitrile analog was described as an eEF2K inhibitor by Devkota et al [34] . A-484954 was uncovered by Abbott laboratories as a specific eEF2K inhibitor, but it is only weakly effective within cells [32] . A recent study created and tested a number of pyrido [2,3-b]pyrimidine-2,4-dione derivatives and found that two such compounds inhibited eEF2K activity with submicromolar IC 50 s in vitro [35] .…”

Section: Inhibitors Of Eef2kmentioning

confidence: 99%

“…Subsequently, NH125, an imidazolium derivative, was reported to be an eEF2K inhibitor [31] , but subsequent studies showed it actually increases eEF2 phosphorylation within cells, probably by acting as a non-specific protein-aggregating agent [32,33] . A thiopyran-dicarbonitrile analog was described as an eEF2K inhibitor by Devkota et al [34] .…”

Section: Inhibitors Of Eef2kmentioning

confidence: 99%

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Eukaryotic elongation factor 2 kinase as a drug target in cancer, and in cardiovascular and neurodegenerative diseases

Proud

2016

Acta Pharmacol Sin

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Eukaryotic elongation factor 2 kinase (eEF2K) is an unusual protein kinase that regulates the elongation stage of protein synthesis by phosphorylating and inhibiting its only known substrate, eEF2. Elongation is a highly energy-consuming process, and eEF2K activity is tightly regulated by several signaling pathways. Regulating translation elongation can modulate the cellular energy demand and may also control the expression of specific proteins. Growing evidence links eEF2K to a range of human diseases, including cardiovascular conditions (atherosclerosis, via macrophage survival) and pulmonary arterial hypertension, as well as solid tumors, where eEF2K appears to play contrasting roles depending on tumor type and stage. eEF2K is also involved in neurological disorders and may be a valuable target in treating depression and certain neurodegenerative diseases. Because eEF2K is not required for mammalian development or cell viability, inhibiting its function may not elicit serious side effects, while the fact that it is an atypical kinase and quite distinct from the vast majority of other mammalian kinases suggests the possibility to develop it into compounds that inhibit eEF2K without affecting other important protein kinases. Further research is needed to explore these possibilities and there is an urgent need to identify and characterize potent and specific small-molecule inhibitors of eEF2K. In this article we review the recent evidence concerning the role of eEF2K in human diseases as well as the progress in developing small-molecule inhibitors of this enzyme.

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“…HCT116 cells, we also treated HCT116 cells expressing shRNA against eEF2K with A484954, a selective eEF2K inhibitor (39). This completely abolished the acidosis-induced eEF2 phosphorylation (Fig.…”

Section: Resultsmentioning

confidence: 99%

Molecular Mechanism for the Control of Eukaryotic Elongation Factor 2 Kinase by pH: Role in Cancer Cell Survival

Xie

Mikolajek

Pigott

et al. 2015

Molecular and Cellular Biology

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f Acidification of the extracellular and/or intracellular environment is involved in many aspects of cell physiology and pathology. Eukaryotic elongation factor 2 kinase (eEF2K) is a Ca 2؉ /calmodulin-dependent kinase that regulates translation elongation by phosphorylating and inhibiting eEF2. Here we show that extracellular acidosis elicits activation of eEF2K in vivo, leading to enhanced phosphorylation of eEF2. We identify five histidine residues in eEF2K that are crucial for the activation of eEF2K during acidosis. Three of them (H80, H87, and H94) are in its calmodulin-binding site, and their protonation appears to enhance the ability of calmodulin to activate eEF2K. The other two histidines (H227 and H230) lie in the catalytic domain of eEF2K. We also identify His108 in calmodulin as essential for activation of eEF2K. Acidification of cancer cell microenvironments is a hallmark of malignant solid tumors. Knocking down eEF2K in cancer cells attenuated the decrease in global protein synthesis when cells were cultured at acidic pH. Importantly, activation of eEF2K is linked to cancer cell survival under acidic conditions. Inhibition of eEF2K promotes cancer cell death under acidosis.

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1-Benzyl-3-cetyl-2-methylimidazolium iodide (NH125) Induces Phosphorylation of Eukaryotic Elongation Factor-2 (eEF2)

Cited by 100 publications

References 30 publications

NH125, an eukaryotic elongation factor 2 kinase inhibitor, radiosensitizes breast cancer by the abrogation of G2/M checkpoint

NH125, an eukaryotic elongation factor 2 kinase inhibitor, radiosensitizes breast cancer by the abrogation of G2/M checkpoint

Eukaryotic elongation factor 2 kinase as a drug target in cancer, and in cardiovascular and neurodegenerative diseases

Molecular Mechanism for the Control of Eukaryotic Elongation Factor 2 Kinase by pH: Role in Cancer Cell Survival

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