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Pharmacological eEF 2K activation promotes cell death and inhibits cancer progression
Author(s) -
De Gassart Aude,
Demaria Olivier,
Panes Rébecca,
Zaffalon Léa,
Ryazanov Alexey G,
Gilliet Michel,
Marti Fabio
Publication year - 2016
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201642194
Subject(s) - library science , gerontology , medicine , computer science
Activation of the elongation factor 2 kinase ( eEF 2K) leads to the phosphorylation and inhibition of the elongation factor eEF 2, 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 ‐ PI s), nelfinavir in particular, trigger a robust activation of eEF 2K leading to the phosphorylation of eEF 2. Beyond its anti‐viral effects, nelfinavir has antitumoral activity and promotes cell death. We show that nelfinavir‐resistant cells specifically evade eEF 2 inhibition. Decreased cell viability induced by nelfinavir is impaired in cells lacking eEF 2K. Moreover, nelfinavir‐mediated anti‐tumoral activity is severely compromised in eEF 2K‐deficient engrafted tumors in vivo . Our findings imply that exacerbated activation of eEF 2K is detrimental for tumor survival and describe a mechanism explaining the anti‐tumoral properties of HIV‐PIs.