1. Pharmacological eEF2K activation promotes cell death and inhibits cancer progression
- Author
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Olivier Demaria, Léa Zaffalon, Michel Gilliet, Rébecca Panes, Alexey G. Ryazanov, Fabio Martinon, and Aude De Gassart
- Subjects
0301 basic medicine ,Drug Resistance ,Gene Expression ,AMP-Activated Protein Kinases ,Biochemistry ,Mice ,Peptide Elongation Factor 2 ,immune system diseases ,Neoplasms ,HIV Protease Inhibitor ,Phosphorylation ,Mice, Knockout ,education.field_of_study ,Nelfinavir ,Cell Death ,TOR Serine-Threonine Kinases ,virus diseases ,Articles ,3. Good health ,Cell biology ,Tumor Burden ,Disease Progression ,Female ,medicine.drug ,Elongation Factor 2 Kinase ,Programmed cell death ,Cell Survival ,Biology ,Mechanistic Target of Rapamycin Complex 1 ,EEF2 ,Cell Line ,03 medical and health sciences ,Genetics ,medicine ,Animals ,Humans ,Viability assay ,education ,Molecular Biology ,Dose-Response Relationship, Drug ,biochemical phenomena, metabolism, and nutrition ,Elongation factor ,Disease Models, Animal ,030104 developmental biology ,Multiprotein Complexes ,Protein Biosynthesis ,AMP-Activated Protein Kinases/metabolism ,Cell Death/drug effects ,Cell Death/genetics ,Cell Survival/drug effects ,Cell Survival/genetics ,Drug Resistance/genetics ,Elongation Factor 2 Kinase/genetics ,Elongation Factor 2 Kinase/metabolism ,Multiprotein Complexes/metabolism ,Nelfinavir/chemistry ,Nelfinavir/pharmacology ,Neoplasms/genetics ,Neoplasms/metabolism ,Neoplasms/pathology ,Peptide Elongation Factor 2/metabolism ,TOR Serine-Threonine Kinases/metabolism ,HIV‐protease inhibitors ,cancer ,cell death ,eEF2K ,mRNA translation ,Elongation Factor-2 Kinase - 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.
- Published
- 2016