Pharmacological eEF2K activation promotes cell death and inhibits cancer progression.

Details

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State: Public
Version: author
Serval ID
serval:BIB_1DC620721907
Type
Article: article from journal or magazin.
Collection
Publications
Title
Pharmacological eEF2K activation promotes cell death and inhibits cancer progression.
Journal
EMBO reports
Author(s)
De Gassart A., Demaria O., Panes R., Zaffalon L., Ryazanov A.G., Gilliet M., Martinon F.
ISSN
1469-3178 (Electronic)
ISSN-L
1469-221X
Publication state
Published
Issued date
10/2016
Peer-reviewed
Oui
Volume
17
Number
10
Pages
1471-1484
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Activation of the elongation factor 2 kinase (eEF2K) leads to the phosphorylation and inhibition of the elongation factor eEF2, reducing mRNA translation rates. Emerging evidence indicates that the regulation of factors involved in protein synthesis may be critical for controlling diverse biological processes including cancer progression. Here we show that inhibitors of the HIV aspartyl protease (HIV-PIs), nelfinavir in particular, trigger a robust activation of eEF2K leading to the phosphorylation of eEF2. Beyond its anti-viral effects, nelfinavir has antitumoral activity and promotes cell death. We show that nelfinavir-resistant cells specifically evade eEF2 inhibition. Decreased cell viability induced by nelfinavir is impaired in cells lacking eEF2K. Moreover, nelfinavir-mediated anti-tumoral activity is severely compromised in eEF2K-deficient engrafted tumors in vivo Our findings imply that exacerbated activation of eEF2K is detrimental for tumor survival and describe a mechanism explaining the anti-tumoral properties of HIV-PIs.

Keywords
AMP-Activated Protein Kinases/metabolism, Animals, Cell Death/drug effects, Cell Death/genetics, Cell Line, Cell Survival/drug effects, Cell Survival/genetics, Disease Models, Animal, Disease Progression, Dose-Response Relationship, Drug, Drug Resistance/genetics, Elongation Factor 2 Kinase/genetics, Elongation Factor 2 Kinase/metabolism, Female, Gene Expression, Humans, Mice, Mice, Knockout, Multiprotein Complexes/metabolism, Nelfinavir/chemistry, Nelfinavir/pharmacology, Neoplasms/genetics, Neoplasms/metabolism, Neoplasms/pathology, Peptide Elongation Factor 2/metabolism, Phosphorylation, Protein Biosynthesis, TOR Serine-Threonine Kinases/metabolism, Tumor Burden, HIV‐protease inhibitors, cancer, cell death, eEF2K, mRNA translation
Pubmed
Web of science
Open Access
Yes
Create date
31/08/2016 21:42
Last modification date
20/08/2019 13:54
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