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.
Elongation factor 2 kinase (eEF2K) is part of an adaptation pathway that enables cells to cope with nutrient deprivation by regulating translation rates. Pharmacological activation of the eEF2K pathway via the anti‐viral drug nelfinavir rewires this stress adaptation program into a response that is detrimental for tumor growth.
The anti‐viral and anti‐tumoral compound nelfinavir is a potent eEF2K activator.
eEF2K activation contributes to NFR‐mediated cell death.
eEF2K deficiency impairs nelfinavir‐mediated antitumoral activity.
EMBO Reports (2016) 17: 1471–1484
- Received February 11, 2016.
- Revision received July 21, 2016.
- Accepted July 22, 2016.
- © 2016 The Authors