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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute Disease
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Animals
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Antineoplastic Agents, Phytogenic / chemistry
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Antineoplastic Agents, Phytogenic / pharmacology
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Blotting, Western
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Cell Line, Tumor
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Dose-Response Relationship, Drug
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Eukaryotic Initiation Factor-4E / chemistry
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Eukaryotic Initiation Factor-4E / metabolism*
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Harringtonines / chemistry
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Harringtonines / pharmacology*
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Homoharringtonine
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Humans
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Interleukin Receptor Common gamma Subunit / deficiency
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Interleukin Receptor Common gamma Subunit / genetics
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Leukemia, Myeloid / drug therapy*
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Leukemia, Myeloid / metabolism
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Leukemia, Myeloid / pathology
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Mice, Inbred NOD
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Mice, Knockout
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Mice, SCID
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Molecular Structure
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Phosphorylation / drug effects
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Proteasome Endopeptidase Complex / metabolism
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Protein Multimerization / drug effects
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Proteolysis / drug effects
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Serine / metabolism*
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Small Ubiquitin-Related Modifier Proteins / metabolism
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Sumoylation / drug effects
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Tumor Cells, Cultured
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Ubiquitins / metabolism
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents, Phytogenic
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Eukaryotic Initiation Factor-4E
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Harringtonines
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Il2rg protein, mouse
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Interleukin Receptor Common gamma Subunit
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SUMO2 protein, human
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SUMO3 protein, human
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Small Ubiquitin-Related Modifier Proteins
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Ubiquitins
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Serine
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Homoharringtonine
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Proteasome Endopeptidase Complex