Pharmacological eEF 2K 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.

Eukaryotic elongation factor 2 kinase upregulates the expression of proteins implicated in cell migration and cancer cell metastasis

“…Thus, the development of specific eEF2K inhibitors with improved pharmacological properties may be valuable in the fight against cancer. However, it is also important to point out that, according to some reports, knocking‐down eEF2K may actually promote tumor growth . Our data also suggest that the levels of expression of eEF2K may serve as a biological marker as to determine the cancer progression stage in patients.…”

“…However, it is also important to point out that, according to some reports, knocking-down eEF2K may actually promote tumor growth. 45,46 Our data also suggest that the levels of expression of eEF2K may serve as a biological marker as to determine the cancer progression stage in patients. Indeed, in certain types of colorectal cancer and melanoma, eEF2K expression levels are higher in normal tissues compared to the cancer ones.…”

Translating the anticancer properties of eEF2K

“…While the ISR is a key response that modulates cellular homeostasis, this pathway did not affect cellular viability in presence of the HIV-PIs. In contrast, we found that NFR-mediated toxicity relied on the activation of the kinase eEF2K 2 (Fig. 1).…”

“…Among these, we recently described that the HIV aspartyl protease inhibitors (HIV-PIs), a family of antiviral drugs, regulate pathways that modulate mRNA translation. 2 The HIV-PIs were designed to specifically target the HIV protease. These safe and orally available molecules have been successfully used for more than 2 decades to decrease viral loads in infected patients.…”

“…Moreover, eEF2K deficiency within tumors impaired NFR-mediated anticancer activity in immunocompromised mice, indicating that pharmacological eEF2K activation drives a tumor intrinsic response that impairs tumor growth. 2 The molecular mechanisms by which NFR triggers eEF2K activation are still unidentified. Main known pathways involved in eEF2K activation, including those downstream of rapamycin, were found to be dispensable, suggesting that NFR mode of action defines a new mechanism of eEF2K activation.…”