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

被引：17

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

共 33 条

[1] Omacetaxine may have a role in chronic myeloid leukaemia eradication through downregulation of Mcl-1 and induction of apoptosis in stem/progenitor cells [J].

Allan, E. K. ;

Holyoake, T. L. ;

Craig, A. R. ;

Jorgensen, H. G. .

LEUKEMIA, 2011, 25 (06) :985-994

[2] Inhibition of Mnk kinase activity by cercosporamide and suppressive effects on acute myeloid leukemia precursors [J].

Altman, Jessica K. ;

Szilard, Amy ;

Konicek, Bruce W. ;

Iversen, Philip W. ;

Kroczynska, Barbara ;

Glaser, Heather ;

Sassano, Antonella ;

Vakana, Eliza ;

Graff, Jeremy R. ;

Platanias, Leonidas C. .

BLOOD, 2013, 121 (18) :3675-3681

[3] Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): a proof-of-principle clinical trial with ribavirin [J].

Assouline, Sarit ;

Culjkovic, Biljana ;

Cocolakis, Eftihia ;

Rousseau, Caroline ;

Beslu, Nathalie ;

Amri, Abdellatif ;

Caplan, Stephen ;

Leber, Brian ;

Roy, Denis-Claude ;

Miller, Wilson H., Jr. ;

Borden, Katherine L. B. .

BLOOD, 2009, 114 (02) :257-260

[4] Inhibitory effects of omacetaxine on leukemic stem cells and BCR-ABL-induced chronic myeloid leukemia and acute lymphoblastic leukemia in mice [J].

Chen, Y. ;

Hu, Y. ;

Michaels, S. ;

Segal, D. ;

Brown, D. ;

Li, S. .

LEUKEMIA, 2009, 23 (08) :1446-1454

[5] Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation [J].

Cortes, Jorge ;

Lipton, Jeff H. ;

Rea, Delphine ;

Digumarti, Raghunadharao ;

Chuah, Charles ;

Nanda, Nisha ;

Benichou, Annie-Claude ;

Craig, Adam R. ;

Michallet, Mauricette ;

Nicolini, Franck E. ;

Kantarjian, Hagop .

BLOOD, 2012, 120 (13) :2573-2580

[6] eIF4E is a central node of an RNA regulon that governs cellular proliferation [J].

Culjkovic, Biljana ;

Topisirovic, Ivan ;

Skrabanek, Lucy ;

Ruiz-Gutierrez, Melisa ;

Borden, Katherine L. B. .

JOURNAL OF CELL BIOLOGY, 2006, 175 (03) :415-426

[7] Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing [J].

Ding, Li ;

Ley, Timothy J. ;

Larson, David E. ;

Miller, Christopher A. ;

Koboldt, Daniel C. ;

Welch, John S. ;

Ritchey, Julie K. ;

Young, Margaret A. ;

Lamprecht, Tamara ;

McLellan, Michael D. ;

McMichael, Joshua F. ;

Wallis, John W. ;

Lu, Charles ;

Shen, Dong ;

Harris, Christopher C. ;

Dooling, David J. ;

Fulton, Robert S. ;

Fulton, Lucinda L. ;

Chen, Ken ;

Schmidt, Heather ;

Kalicki-Veizer, Joelle ;

Magrini, Vincent J. ;

Cook, Lisa ;

McGrath, Sean D. ;

Vickery, Tammi L. ;

Wendl, Michael C. ;

Heath, Sharon ;

Watson, Mark A. ;

Link, Daniel C. ;

Tomasson, Michael H. ;

Shannon, William D. ;

Payton, Jacqueline E. ;

Kulkarni, Shashikant ;

Westervelt, Peter ;

Walter, Matthew J. ;

Graubert, Timothy A. ;

Mardis, Elaine R. ;

Wilson, Richard K. ;

DiPersio, John F. .

NATURE, 2012, 481 (7382) :506-510

[8] Insulin and phorbol ester stimulate initiation factor eIF-4E phosphorylation by distinct pathways in Chinese hamster ovary cells overexpressing the insulin receptor [J].

Flynn, A ;

Proud, CG .

EUROPEAN JOURNAL OF BIOCHEMISTRY, 1996, 236 (01) :40-47

[9] Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes [J].

Friesner, Richard A. ;

Murphy, Robert B. ;

Repasky, Matthew P. ;

Frye, Leah L. ;

Greenwood, Jeremy R. ;

Halgren, Thomas A. ;

Sanschagrin, Paul C. ;

Mainz, Daniel T. .

JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (21) :6177-6196

[10] eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression [J].

Furic, Luc ;

Rong, Liwei ;

Larsson, Ola ;

Koumakpayi, Ismael Herve ;

Yoshida, Kaori ;

Brueschke, Andrea ;

Petroulakis, Emmanuel ;

Robichaud, Nathaniel ;

Pollak, Michael ;

Gaboury, Louis A. ;

Pandolfi, Pier Paolo ;

Saad, Fred ;

Sonenberg, Nahum .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (32) :14134-14139

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