Abstract
Eukaryotic elongation factor 2 kinase (eEF2K) inhibits the elongation stage of protein synthesis by phosphorylating its only known substrate, eEF2. eEF2K is tightly regulated by nutrient-sensitive signalling pathways. For example, it is inhibited by signalling through mammalian target of rapamycin complex 1 (mTORC1). It is therefore activated under conditions of nutrient deficiency.Here we show that inhibiting eEF2K or knocking down its expression renders cancer cells sensitive to death under nutrient-starved conditions, and that this is rescued by compounds that block protein synthesis. This implies that eEF2K protects nutrient-deprived cells by inhibiting protein synthesis. Cells in which signalling through mTORC1 is highly active are very sensitive to nutrient withdrawal. Inhibiting mTORC1 protects them. Our data reveal that eEF2K makes a substantial contribution to the cytoprotective effect of mTORC1 inhibition.eEF2K is also reported to promote another potentially cytoprotective process, autophagy. We have used several approaches to test whether inhibition or loss of eEF2K affects autophagy under a variety of conditions. We find no evidence that eEF2K is involved in the activation of autophagy in the cell types we have studied.We conclude that eEF2K protects cancer cells against nutrient starvation by inhibiting protein synthesis rather than by activating autophagy.
Highlights
Recent work has identified eukaryotic elongation factor 2 kinase as playing a key cytoprotective role in cancer cells under conditions of nutrient starvation [1], implying that inhibiting its activity may offer a novel therapeutic avenue in oncology
To assess whether the inhibition of eukaryotic elongation factor 2 kinase (eEF2K) promotes cell death by disinhibiting translation elongation, we explored the effect of reimposing inhibition of protein synthesis using two distinct translation inhibitors, cycloheximide (CHX, which inhibits elongation) and Harringtonine
The present data add further support to the concept that eEF2K plays an important role in enabling cancer cells to survive glucose starvation, in particular by extending earlier work to show that (i) pharmacological inhibition of eEF2K, like knocking down its expression, impairs the ability of cells to withstand glucose starvation, (ii) this role extends to cancer cell types other than those previously tested and (iii) that restoring inhibition of elongation in cells where eEF2K has been inhibited ‘rescues’ them from cell death, indicating that eEF2K protects cells by inhibiting protein synthesis
Summary
Recent work has identified eukaryotic elongation factor 2 kinase (eEF2K) as playing a key cytoprotective role in cancer cells under conditions of nutrient starvation [1], implying that inhibiting its activity may offer a novel therapeutic avenue in oncology. Our data provide strong evidence that eEF2K does so by inhibiting protein synthesis, and do not support the idea that eEF2K regulates autophagy, at least in the cell types we have studied. These findings are important given the growing interest in eEF2K as a target for cancer therapy
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