Small-molecule induction of phospho-eIF4E sumoylation and degradation via targeting its phosphorylated serine 209 residue

Oncotarget. 2015 Jun 20;6(17):15111-21. doi: 10.18632/oncotarget.3615.

Abstract

As phospho-eIF4E (p-eIF4E), unlike total eIF4E (t-eIF4E) essential for normal cells, is specifically required by cancer cells, it is an attractive, yet unrealized, target for anti-tumor intervention. Here we identify a small molecule, homoharringtonine (HHT), that antagonizes p-eIF4E function and eradicates acute myeloid leukemia (AML) expressing high level of p-eIF4E in vitro and in vivo. HHT selectively reduces p-eIF4E levels of leukemia cells without affecting t-eIF4E. HHT targets the phosphorylated serine 209 residue of p-eIF4E and induces p-eIF4E oligomerization, which enhances its interaction with the small ubiquitin-like protein modifier (SUMO)-conjugating enzyme UBC9, resulting in proteasome-dependent degradation of p-eIF4E via SUMO2/3-mediated SUMOylation. These results suggest that the phosphorylated serine 209 residue of p-eIF4E might be a potential target for developing small molecule-based new therapies for leukemia.

Keywords: acute myeloid leukemia; homoharritonine; phospho-eIF4E; proteasome-dependent degradation; small molecular inhibitor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Blotting, Western
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Eukaryotic Initiation Factor-4E / chemistry
  • Eukaryotic Initiation Factor-4E / metabolism*
  • Harringtonines / chemistry
  • Harringtonines / pharmacology*
  • Homoharringtonine
  • Humans
  • Interleukin Receptor Common gamma Subunit / deficiency
  • Interleukin Receptor Common gamma Subunit / genetics
  • Leukemia, Myeloid / drug therapy*
  • Leukemia, Myeloid / metabolism
  • Leukemia, Myeloid / pathology
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Molecular Structure
  • Phosphorylation / drug effects
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Multimerization / drug effects
  • Proteolysis / drug effects
  • Serine / metabolism*
  • Small Ubiquitin-Related Modifier Proteins / metabolism
  • Sumoylation / drug effects
  • Tumor Cells, Cultured
  • Ubiquitins / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents, Phytogenic
  • Eukaryotic Initiation Factor-4E
  • Harringtonines
  • Il2rg protein, mouse
  • Interleukin Receptor Common gamma Subunit
  • SUMO2 protein, human
  • SUMO3 protein, human
  • Small Ubiquitin-Related Modifier Proteins
  • Ubiquitins
  • Serine
  • Homoharringtonine
  • Proteasome Endopeptidase Complex