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    刘宇博

    • 教授     博士生导师   硕士生导师
    • 性别:男
    • 毕业院校:大连理工大学
    • 学位:博士
    • 所在单位:化工海洋与生命学院
    • 学科:生物化学与分子生物学. 生物化工. 化学生物学
    • 办公地点:大连理工大学 盘锦校区 生命与医药学院 F03-314
    • 联系方式:liuyubo@dlut.edu.cn
    • 电子邮箱:liuyubo@dlut.edu.cn

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    Mechanisms of anti-leukemic activity of the Bcl-2 homology domain-3 mimetic S1

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    论文类型:期刊论文

    发表时间:2013-09-01

    发表刊物:BIOMEDICINE & PHARMACOTHERAPY

    收录刊物:PubMed、SCIE、Scopus

    卷号:67

    期号:7

    页面范围:583-591

    ISSN号:0753-3322

    关键字:BH3 mimetic; AML; Bak-dependent

    摘要:Most of leukemia exhibits inherent overexpressed Bcl-2-like proteins. Small molecule S1 is a BH3 mimetic discovered by our previous studies. The aim of this study is to dissect the details of apoptosis signaling induced by S1 in acute myeloid leukaemia (AML) cells and to provide a molecular basis for the use of S1 in AML treatment. The anti-leukemic activity of S1 was evaluated in three cultured AML cell lines and eight patient samples. S1 induced apoptosis via an intrinsic apoptosis pathway by the disruption of protein-protein interactions of Bcl-2 family members and triggered the activation of Bax and Bak in AML cells. For the first time, we report that S1 can release pro-apoptotic protein from Bcl-XL and selectively inhibits colony formation of primary AML cells. Bak activation and release determined S1 sensitivity in AML cells. Furthermore, S1-induced apoptosis was largely reduced in cells with shRNA-mediated downregulation of Bak but not Bax. The combination of S1 with PD98059 can inhibit Bcl-2 phosphorylation and enhance Bak release from Bcl-2. Our study identified Bak as a key mediator of S1-induced intrinsic apoptosis in AML cells. Moreover, our data suggest that Bcl-2 phosphorylation plays an anti-apoptotic role in S1-induced apoptosis. This study could contribute not only to the future clinical development of S1, but also the rational use of other pan-Bcl-2 inhibitors, alone or in combination with kinase inhibitor-based strategies. (C) 2013 Elsevier Masson SAS. All rights reserved.