Bcl-2 phosphorylation confers resistance on chronic lymphocytic leukaemia cells to the BH3 mimetics ABT-737, ABT-263 and ABT-199 by impeding direct binding
发表时间：2019-03-13
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- 论文类型：
- 期刊论文
- 第一作者：
- Song, Ting
- 通讯作者：
- Zhang, ZC (reprint author), Dalian Univ Technol, Sch Chem, State Key Lab Fine Chem, Dalian 116024, Peoples R China.
- 合写作者：
- Chai, Gaobo,Liu, Yubo,Yu, Xiaoyan,Wang, Ziqian,Zhang, Zhichao
- 发表时间：
- 2016-02-01
- 发表刊物：
- BRITISH JOURNAL OF PHARMACOLOGY
- 收录刊物：
- SCIE、PubMed、Scopus
- 文献类型：
- J
- 卷号：
- 173
- 期号：
- 3
- 页面范围：
- 471-483
- ISSN号：
- 0007-1188
- 摘要：
- Background and PurposeAlthough the ongoing clinical trials of ABT-263 and ABT-199 in chronic lymphocytic leukaemia (CLL) have indicated that BH3 mimetics hold considerable promise, understanding the mechanism of CLL resistance to BH3 mimetics remains a challenge. Experimental ApproachThe LD50 values of ABT-737, ABT-263 and ABT-199 in a number of primary CLL cells from 40 patients, were determined. The levels of Bcl-2 family proteins, including phosphorylated Bcl-2 (pBcl-2) and their interactions were measured by immunoblotting and co-immunoprecipitation. In vitro binding assays were performed by isothermal titration calorimetry and ELISA. BH3 profiling in isolated mitochondria was analysed. Key ResultsThe ratio of (Mcl-1 + pBcl-2) to Bcl-2 expression provided the most significant predictive marker for the cytotoxic potential of ABT-737, ABT-263 and ABT-199 in the panel of CLL samples. Mechanistically, pBcl-2 inhibited the effects of the ABT compounds on the displacement of Bax and Bim from Bcl-2, thereby suppressing mitochondrial apoptosis. The ABT compounds exhibited 100-300-fold lower binding affinity to the glutamic acid, phosphomimetic, mutant of Bcl-2 (T69E, S70E and S87E; EEE-Bcl-2). BH3 peptides exhibited different rank orders of binding affinities to full-length WT-Bcl-2 and full-length EEE-Bcl-2. Conclusions and ImplicationsOur study suggested that a structural alteration in the BH3-binding groove was induced by phosphorylation of Bcl-2. Our data also provided a framework to overcome resistance of CLL cells to the ABT compounds by combining pBcl-2 kinase inhibitors with the ABT compounds.
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