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

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.

• Authors: Ying Gu, Hong Zhou, Yichao Gan, Jiawei Zhang, Jianghua Chen, Xiaoxian Gan, Hongzhi Li, Weiwei Zheng, Zhipeng Meng, Xiaoxiao Ma, Xichun Wang, Xiaohua Xu, Ganyu Xu, Xiaoya Lu, Yun Liang, Xuzhao Zhang, Xinliang Lu, Wendong Huang, Rongzhen Xu
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 17 Pg. 15111-21 (Jun 20 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25915158 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Acute Disease
• Animals
• Antineoplastic Agents, Phytogenic (chemistry, pharmacology)
• Blotting, Western
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Eukaryotic Initiation Factor-4E (chemistry, metabolism)
• Harringtonines (chemistry, pharmacology)
• Homoharringtonine
• Humans
• Interleukin Receptor Common gamma Subunit (deficiency, genetics)
• Leukemia, Myeloid (drug therapy, metabolism, 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