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

被引：16

作者：

Gu, Ying ^{[1
,2
,3
]}

Zhou, Hong ^{[1
,2
]}

Gan, Yichao ^{[1
,2
]}

Zhang, Jiawei ^{[2
,3
]}

Chen, Jianghua ^{[1
,2
]}

Gan, Xiaoxian ^{[3
,4
]}

Li, Hongzhi ^{[5
]}

Zheng, Weiwei ^{[1
,2
]}

Meng, Zhipeng ^{[3
]}

Ma, Xiaoxiao ^{[3
]}

Wang, Xichun ^{[3
]}

Xu, Xiaohua ^{[1
]}

Xu, Ganyu ^{[3
]}

Lu, Xiaoya ^{[1
,2
]}

Liang, Yun ^{[1
]}

Zhang, Xuzhao ^{[1
]}

Lu, Xinliang ^{[2
]}

Huang, Wendong ^{[3
]}

Xu, Rongzhen ^{[1
,2
]}

机构：

[1] Zhejiang Univ, Dept Hematol, Key Lab Canc Prevent & Intervent, China Natl Minist Educ,Affiliated Hosp 2, Hangzhou 310009, Zhejiang, Peoples R China

[2] Zhejiang Univ, Sch Med, Affiliated Hosp 2, Canc Inst, Hangzhou 310009, Zhejiang, Peoples R China

[3] City Hope Natl Med Ctr, Div Mol Diabet Res, Dept Diabet & Metab Dis Res, Beckman Res Inst, Duarte, CA 91010 USA

[4] Zhejiang Acad Med Sci, Hangzhou 310012, Zhejiang, Peoples R China

[5] City Hope Natl Med Ctr, Beckman Res Inst, Dept Mol Med, Duarte, CA 91010 USA

来源：

ONCOTARGET | 2015年 / 6卷 / 17期

基金：

中国国家自然科学基金;

关键词：

phospho-eIF4E; homoharritonine; small molecular inhibitor; proteasome-dependent degradation; acute myeloid leukemia; ACUTE MYELOID-LEUKEMIA; CHRONIC-PHASE; FACTOR EIF4E; STEM-CELLS; HOMOHARRINGTONINE; TRANSLATION; THERAPY; OMACETAXINE; TRANSFORMATION; TUMORIGENESIS;

D O I：

10.18632/oncotarget.3615

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：15111 / 15121

页数：11

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