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

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.
Mesh Terms:
Acute Disease, Animals, Antineoplastic Agents, Phytogenic, Blotting, Western, Cell Line, Tumor, Dose-Response Relationship, Drug, Eukaryotic Initiation Factor-4E, Harringtonines, Homoharringtonine, Humans, Interleukin Receptor Common gamma Subunit, Leukemia, Myeloid, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Molecular Structure, Phosphorylation, Proteasome Endopeptidase Complex, Protein Multimerization, Proteolysis, Serine, Small Ubiquitin-Related Modifier Proteins, Sumoylation, Tumor Cells, Cultured, Ubiquitins, Xenograft Model Antitumor Assays
Oncotarget
Date: Jun. 20, 2015
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