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学科主题: 临床医学
题名:
Thiamet-G-mediated inhibition of O-GlcNAcase sensitizes human leukemia cells to microtubule-stabilizing agent paclitaxel
作者: 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
发表日期: 2014-10-24
DOI: 10.1016/j.bbrc.2014.09.097
卷: 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
所属项目编号: 7132050 ; 81201873 ; 81470368 ; 2011CB504303
项目资助者: Beijing Natural Science Foundation ; NSFC ; 973 program
WOS记录号: WOS:000350267500018
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/58871
Appears in Collections:北京大学临床肿瘤学院_淋巴肿瘤内科_期刊论文

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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

Recommended Citation:
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.
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