Oncotarget

Research Papers:

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

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 and Rongzhen Xu

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Oncotarget. 2015; 6:15111-15121. https://doi.org/10.18632/oncotarget.3615

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Abstract

Ying Gu1,2,3,*, Hong Zhou1,2,*, Yichao Gan1,2,*, Jiawei Zhang2,3,*, Jianghua Chen1,2, Xiaoxian Gan3,4, Hongzhi Li5, Weiwei Zheng1,2, Zhipeng Meng3, Xiaoxiao Ma3, Xichun Wang3, Xiaohua Xu1, Ganyu Xu3, Xiaoya Lu1,2, Yun Liang1, Xuzhao Zhang1, Xinliang Lu2, Wendong Huang3, Rongzhen Xu1,2

1Department of Hematology, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China

2Cancer Institute, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China

3Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA

4Zhejiang Academy of Medical Sciences, Hangzhou, 310012, China

5Department of Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA

*These authors have contributed equally to this work

Correspondence to:

Rongzhen Xu, e-mail: [email protected]

Wendong Huang, e-mail: [email protected]

Keywords: phospho-eIF4E, homoharritonine, small molecular inhibitor, proteasome-dependent degradation, acute myeloid leukemia

Received: February 04, 2015     Accepted: March 14, 2015     Published: April 10, 2015

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.


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