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.
Highlights
Acute myeloid leukemia (AML), the most common acute leukemia in adults, is a heterogeneous group of clonal disorders characterized by an abnormal proliferation of myeloid stem/progenitor cells and subsequent bone marrow (BM) failure [1,2,3,4]
We demonstrate that it is possible to directly target p-eIF4E, an unrealized attractive target for anti-tumor intervention, using small molecules
We found www.impactjournals.com/oncotarget that HHT preferentially targets the loop of 201–212aa of p-eIF4E but not of total eIF4E (t-eIF4E), which in turn induces oligomerization, SUMO2/3-mediated SUMOylation and subsequent proteasome-dependent degradation of p-eIF4E proteins
Summary
Acute myeloid leukemia (AML), the most common acute leukemia in adults, is a heterogeneous group of clonal disorders characterized by an abnormal proliferation of myeloid stem/progenitor cells and subsequent bone marrow (BM) failure [1,2,3,4]. There is an urgent need for more potent and safer therapies against leukemia-associated targets for AML. Consistent with this, studies have shown a positive correlation between increased eIF4E phosphorylation and cell proliferation [17, 18], and highly phosphorylated eIF4E was observed in a variety of cancers [10, 19]. Recent studies have shown that inhibiting p-eIF4E with small molecule inhibitors of MNK that phosphorylates eIF4E, exhibited a potent inhibition for leukemia [19, 20]. We reasoned that small molecules that directly target the p-eIF4E but not eIF4E would exhibit more potent and safer therapeutic effects for cancer
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