title: Pharmacological eEF2K activation promotes cell death and inhibits cancer progression.
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.
authors: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors: Aude
authors: A
authors: De Gassart
authors: Department of Dermatology, CHUV, Lausanne, Switzerland.
authors: Olivier
authors: O
authors: Demaria
authors: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors: Rébecca
authors: R
authors: Panes
authors: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors: Léa
authors: L
authors: Zaffalon
authors: Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers The State University of New Jersey, Piscataway, NJ, USA.
authors: Alexey G
authors: AG
authors: Ryazanov
authors: Department of Dermatology, CHUV, Lausanne, Switzerland.
authors: Michel
authors: M
authors: Gilliet
authors: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland fabio.martinon@unil.ch.
authors: Fabio
authors: 0000-0002-6969-822X
authors: F
authors: Martinon
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics; D054736:Elongation Factor 2 Kinase / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism; D019888:Nelfinavir / Q000737:chemistry / Q000494:pharmacology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D020652:Peptide Elongation Factor 2 / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D047368:Tumor Burden
chemical_list: D046912:Multiprotein Complexes; D020652:Peptide Elongation Factor 2; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C517690:Eef2k protein, mouse; D054736:Elongation Factor 2 Kinase; D055372:AMP-Activated Protein Kinases; D019888:Nelfinavir
keywords: HIV‐protease inhibitors; cancer; cell death; eEF2K; mRNA translation