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Pharmacological eEF2K activation promotes cell death and inhibits cancer progression

Aude De Gassart1, Olivier Demaria2, Rébecca Panes1

  • 1Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.

EMBO Reports
|August 31, 2016
PubMed

Insights

HIV protease inhibitors like nelfinavir activate elongation factor 2 kinase (eEF2K), inhibiting protein synthesis. This eEF2K activation is crucial for nelfinavir's anti-cancer effects, making it a target for cancer therapy.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Cancer Research

Background:

  • Protein synthesis regulation is vital for biological processes, including cancer progression.
  • Elongation factor 2 kinase (eEF2K) phosphorylates and inhibits elongation factor eEF2, slowing mRNA translation.

Purpose of the Study:

  • To investigate the role of eEF2K in the anti-tumoral activity of HIV protease inhibitors (HIV-PIs).
  • To elucidate the mechanism behind nelfinavir's anti-cancer effects.

Main Methods:

  • Utilized nelfinavir, an HIV-PI, to study its effects on eEF2K activation and eEF2 phosphorylation.
  • Examined nelfinavir-resistant cell lines to understand resistance mechanisms.
  • Assessed cell viability and tumor growth in eEF2K-deficient models (in vitro and in vivo).

Main Results:

  • Nelfinavir robustly activates eEF2K, leading to eEF2 phosphorylation and inhibition.
  • Nelfinavir-resistant cells evade eEF2 inhibition.
  • Nelfinavir's anti-tumoral effects, including reduced cell viability and tumor growth, are dependent on eEF2K.
  • eEF2K deficiency significantly compromises nelfinavir's anti-cancer activity in vivo.

Conclusions:

  • Exacerbated eEF2K activation is detrimental to tumor cell survival.
  • The anti-tumoral properties of HIV-PIs like nelfinavir are mediated, in part, by eEF2K activation.
  • Targeting eEF2K presents a potential therapeutic strategy for cancer treatment.
Keywords:
HIV‐protease inhibitorscancercell deatheEF2KmRNA translation

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