Blockade of the interaction between Bcr-Abl and PTB1B by small molecule SBF-1 to overcome imatinib-resistance of chronic myeloid leukemia cells
Blockade of the interaction between Bcr-Abl and PTB1B by small molecule SBF-1 to overcome imatinib-resistance of chronic myeloid leukemia cells
复制标题
通过小分子 SBF-1 阻断 Bcr-Abl 和 PTB1B 之间的相互作用，以克服慢性粒细胞白血病细胞对伊马替尼的耐药性。
DOI：
10.1016/j.canlet.2015.12.014
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发表时间：
2016-03-01
期刊：
影响因子：
9.7
通讯作者：
Xu, Qiang
中科院分区：
文献类型：
--
作者：
Elgehama, Ahmed;Chen, Wei;Xu, Qiang
细胞株K562及其伊马替尼耐药株K562/G均可诱导细胞凋亡，但对细胞周期停滞无影响。它还抑制PI3K/Akt通路成员的激活，如PI3K和Akt，以及下游靶标mTOR和Bcl-2。SBF-1以浓度和时间依赖的方式诱导bcr-Abl蛋白降解。通过下拉实验发现，SBF-1同时与BCR-Ab1和PTP1B结合，并破坏了它们之间的相互作用。SBF-1通过溶酶体途径通过泛素化途径激活BCR-Abl的降解。综合这些发现，本研究首次提出阻断BCR-Abl和PTP1B之间的相互作用可能是治疗CML，特别是对BCR-Abl激酶抑制剂伊马替尼耐药的CML的一种可行的策略。我们的研究还表明，SBF-1可能是新型抗CML治疗药物的先导化合物。(C)2015爱思唯尔爱尔兰有限公司。保留所有权利。
cell line K562 and its imatinib-resistant form K562/G. SBF-1 induced apoptosis in both cell lines without any effect on cell cycle arrest. It also inhibited the activation of PI3K/Akt pathway members, such as PI3K and Akt, as well as downstream targets mTOR and Bcl-2. Moreover, the degradation of the Bcr-Abl protein was induced by SBF-1 in a concentration- and time-dependent manner. Using a pull-down assay, SBF-1 was found to bind to both Bcr-Abl and PTP1B and disrupted the interaction between them. SBF-1 triggered the degradation of Bcr-Abl through ubiquitination via the lysosome pathway. Taking together these findings, this study, for the first time, suggests that the blockade of the interaction between Bcr-Abl and PTP1B may be a feasible strategy for the treatment of CML, especially CML with resistance to Bcr-Abl kinase inhibitor imatinib. Our study also indicates that SBF-1 may serve as a leading compound for novel anti-CML therapeutic agents. (C) 2015 Elsevier Ireland Ltd. All rights reserved.