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Thiamet-G-mediated inhibition of O-GlcNAcase sensitizes human leukemia cells to microtubule-stabilizing agent paclitaxel
Ding, Ning1; Ping, Lingyan1; Shi, Yunfei2; Feng, Lixia1; Zheng, Xiaohui1; Song, Yuqin1; Zhu, Jun1
关键词O-GlcNAcase Leukemia Paclitaxel Thiamet-G Microtubule
刊名BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
2014-10-24
DOI10.1016/j.bbrc.2014.09.097
453期:3页:392-397
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Biochemistry & Molecular Biology ; Biophysics
研究领域[WOS]Biochemistry & Molecular Biology ; Biophysics
关键词[WOS]CARDIOVASCULAR-SYSTEM ; NUTRIENT REGULATION ; CANCER ; TAU ; PHOSPHORYLATION ; GLCNACYLATION ; GLYCOSYLATION ; TRANSCRIPTION ; APOPTOSIS ; BIOLOGY
英文摘要

Although the microtubule-stabilizing agent paclitaxel has been widely used for treatment of several cancer types, particularly for the malignancies of epithelia origin, it only shows limited efficacy on hematological malignancies. Emerging roles of O-GlcNAcylation modification of proteins in various cancer types have implicated the key enzymes catalyzing this reversible modification as targets for cancer therapy. Here, we show that the highly selective O-GlcNAcase (OGA) inhibitor thiamet-G significantly sensitized human leukemia cell lines to paclitaxel, with an approximate 10-fold leftward shift of IC50. Knockdown of OGA by siRNAs or inhibition of OGA by thiamet-G did not influence the cell viability. Furthermore, we demonstrated that thiamet-G binds to OGA in competition with 4-methylumbelliferyl N-acetyl-beta-D-glucosaminide dehydrate, an analogue of O-GlcNAc UDP, thereby suppressing the activity of OGA. Importantly, inhibition of OGA by thiamet-G decreased the phosphorylation of microtubule-associated protein Tau and caused alterations of microtubule network in cells. It is noteworthy that paclitaxel combined with thiamet-G resulted in more profound perturbations on microtubule stability than did either one alone, which may implicate the underlying mechanism of thiamet-G-mediated sensitization of leukemia cells to paclitaxel. These findings thus suggest that a regimen of paclitaxel combined with OGA inhibitor might be more effective for the treatment of human leukemia. (C) 2014 Elsevier Inc. All rights reserved.

语种英语
WOS记录号WOS:000350267500018
项目编号7132050 ; 81201873 ; 81470368 ; 2011CB504303
资助机构Beijing Natural Science Foundation ; NSFC ; 973 program
引用统计
被引频次:2[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/58871
专题北京大学临床肿瘤学院_淋巴肿瘤内科
北京大学临床肿瘤学院_病理科
作者单位1.Peking Univ, Canc Hosp & Inst, Dept Lymphoma, Key Lab Carcinogenesis & Translat Res,Minist Educ, Beijing 100142, Peoples R China
2.Peking Univ, Canc Hosp & Inst, Dept Pathol, Key Lab Carcinogenesis & Translat Res,Minist Educ, Beijing 100142, Peoples R China
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GB/T 7714
Ding, Ning,Ping, Lingyan,Shi, Yunfei,et al. Thiamet-G-mediated inhibition of O-GlcNAcase sensitizes human leukemia cells to microtubule-stabilizing agent paclitaxel[J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,2014,453(3):392-397.
APA Ding, Ning.,Ping, Lingyan.,Shi, Yunfei.,Feng, Lixia.,Zheng, Xiaohui.,...&Zhu, Jun.(2014).Thiamet-G-mediated inhibition of O-GlcNAcase sensitizes human leukemia cells to microtubule-stabilizing agent paclitaxel.BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,453(3),392-397.
MLA Ding, Ning,et al."Thiamet-G-mediated inhibition of O-GlcNAcase sensitizes human leukemia cells to microtubule-stabilizing agent paclitaxel".BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 453.3(2014):392-397.
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