Bim 的分布决定了 Mcl-1 表达的骨髓瘤细胞中 Mcl-1 与 Bcl-xL/Bcl-2 的依赖性或共依赖性。
Distribution of Bim determines Mcl-1 dependence or codependence with Bcl-xL/Bcl-2 in Mcl-1-expressing myeloma cells.
机构信息
Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA.
出版信息
Blood. 2011 Aug 4;118(5):1329-39. doi: 10.1182/blood-2011-01-327197. Epub 2011 Jun 9.
Abstract
Dependence on Bcl-2 proteins is a common feature of cancer cells and provides a therapeutic opportunity. ABT-737 is an antagonist of antiapoptotic Bcl-2 proteins and therefore is a good predictor of Bcl-x(L)/Bcl-2 dependence. Surprisingly, analysis of Mcl-1-dependent multiple myeloma cell lines revealed codependence on Bcl-2/Bcl-x(L) in half the cells tested. Codependence is not predicted by the expression level of antiapoptotic proteins, rather through interactions with Bim. Consistent with these findings, acquired resistance to ABT-737 results in loss of codependence through redistribution of Bim to Mcl-1. Overall, these results suggest that complex interactions, and not simply expression patterns of Bcl-2 proteins, need to be investigated to understand Bcl-2 dependence and how to better use agents, such as ABT-737.
摘要
对 Bcl-2 蛋白的依赖是癌细胞的一个共同特征，为治疗提供了机会。ABT-737 是抗凋亡 Bcl-2 蛋白的拮抗剂，因此是 Bcl-x(L)/Bcl-2 依赖性的良好预测因子。令人惊讶的是，对依赖 Mcl-1 的多发性骨髓瘤细胞系的分析表明，在测试的一半细胞中存在对 Bcl-2/Bcl-x(L)的共依赖性。这种共依赖性不是通过抗凋亡蛋白的表达水平预测的，而是通过与 Bim 的相互作用预测的。与这些发现一致，对 ABT-737 的获得性耐药导致通过将 Bim 重新分配到 Mcl-1 来丧失共依赖性。总的来说，这些结果表明，需要研究复杂的相互作用，而不仅仅是 Bcl-2 蛋白的表达模式，以了解 Bcl-2 依赖性以及如何更好地使用 ABT-737 等药物。
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