The cap-translation inhibitor 4EGI-1 induces mitochondrial dysfunction via regulation of mitochondrial dynamic proteins in human glioma U251 cells

Neurochem Int. 2015 Nov;90:98-106. doi: 10.1016/j.neuint.2015.07.019. Epub 2015 Jul 26.

Abstract

Translation initiation factors (eIFs) are over-activated in many human cancers and may contribute to their progression. The small molecule 4EGI-1, a potent inhibitor of translation initiation through disrupting eIF4E/eIF4G interaction, has been shown to exert anti-cancer effects in human cancer cells. The goal of the present study was to evaluate the anti-cancer effects of 4EGI-1 in human glioma U251 cells. We found that 4EGI-1 impaired the assembly of the eIF4F complex, and inhibited proliferation of U251 cells via inducing apoptosis. 4EGI-1 treatment induced collapse of mitochondrial membrane potential (MMP) and production of intracellular reactive oxygen species (ROS), which were prevented by the ROS scavenger N-acetyl-cysteine (NAC). In addition, 4EGI-1 inhibited mitochondrial ATP synthesis via suppressing complex I activity, but had no effects on mitochondrial biogenesis. The results of fluorescence staining showed that 4EGI-1 indeed fragmented the mitochondrial network of U251 cells. We found a significant decrease in optic atrophy type 1 (Opa-1) and mitofusin 1 (Mfn-1) related to fusion proteins as well as an increase in fission protein dynamin-related protein 1 (Drp-1). Furthermore, the anti-cancer effects of 4GI-1 were partially nullified by knock down of Drp-1 using siRNA. These data indicate that the use of inhibitors that directly target the translation initiation complex eIF4F could represent a potential novel approach for human glioma therapy.

Keywords: 4EGI-1; Fission; Fusion; Glioma; Mitochondrial biogenesis; U251 cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Glioma / drug therapy
  • Humans
  • Hydrazones / pharmacology*
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondrial Dynamics / drug effects*
  • Protein Biosynthesis / drug effects*
  • Protein Synthesis Inhibitors / pharmacology*
  • Thiazoles / pharmacology*

Substances

  • 4EGI-1 compound
  • Hydrazones
  • Protein Synthesis Inhibitors
  • Thiazoles