Mcl-1 antagonism is a potential therapeutic strategy in a subset of solid cancers
Mcl-1 antagonism is a potential therapeutic strategy in a subset of solid cancers
复制标题
DOI：
10.1016/j.yexcr.2014.11.022
复制
发表时间：
2015-03-15
影响因子：
3.7
通讯作者：
Galvani, Arturo
中科院分区：
文献类型：
--
作者：
Modugno, Michele;Banfi, Patrizia;Galvani, Arturo
癌细胞存活通常依赖于与BH 3-结构域促凋亡细胞蛋白结合并结合的促存活蛋白Bcl-2家族成员的水平升高。抑制促存活和促凋亡BcI-2家族成员之间的蛋白质相互作用的小分子（所谓的“BH 3模拟物”）具有潜在的治疗价值，如用ABT-263（navitoclax）（一种BcI-2/BcI-xL拮抗剂）和最近用GDC-0199/ABT-199（一种更有选择性的BcI-2拮抗剂）获得的临床结果所示。在这里，我们报告了促生存蛋白Mcl-1对一组代表不同肿瘤类型的实体癌细胞系的功能作用的研究结果。我们观察到小干扰RNA（siRNA）沉默Mcl-1表达显著降低了几乎30%的测试细胞系的活力并诱导了细胞凋亡，包括肺腺癌和乳腺癌以及胶质母细胞瘤衍生系。最重要的是，我们通过显示用特异性BH 3肽对抗分离的线粒体的Mcl-1功能的拮抗作用诱导巴克寡聚化和细胞色素c释放，从而证明来自Mcl-1敏感细胞的线粒体依赖于Mcl-1的完整性，并且拮抗Mcl-1功能足以诱导细胞凋亡，从而为这种敏感性提供了机制基础。因此，我们的研究结果进一步支持将Mcl-1视为许多实体癌中的治疗靶点，并支持开发该蛋白质的小分子BH 3模拟物拮抗剂的基本原理。(C)2014爱思唯尔公司All rights reserved.
Cancer cell survival is frequently dependent on the elevated levels of members of the BcI-2 family of prosurvival proteins that bind to and inactivate BH3-domain pro-apoptotic cellular proteins. Small molecules that inhibit the protein protein interactions between prosurvival and proapoptotic BcI-2 family members (so-called "BH3 mimetics") have a potential therapeutic value, as indicated by clinical findings obtained with ABT-263 (navitoclax), a BcI-2/BcI-xL antagonist, and more recently with GDC-0199/ABT-199, a more selective antagonist of BcI-2. Here, we report study results of the functional role of the prosurvival protein Mcl-1 against a panel of solid cancer cell lines representative of different tumor types. We observed silencing of Mcl-1 expression by small interfering RNAs (siRNAs) significantly reduced viability and induced apoptosis in almost 30% of cell lines tested, including lung and breast adenocarcinoma, as well as glioblastoma derived lines. Most importantly, we provide a mechanistic basis for this sensitivity by showing antagonism of Mcl-1 function with specific BH3 peptides against isolated mitochondria induces Bak oligomerization and cytochrome c release, therefore demonstrating that mitochondria from Mcl-l-sensitive cells depend on Mcl-1 for their integrity and that antagonizing Mcl-1 function is sufficient to induce apoptosis. Thus, our results lend further support for considering Mcl-1 as a therapeutic target in a number of solid cancers and support the rationale for development of small molecule BH3-mimetics antagonists of this protein. (C) 2014 Elsevier Inc. All rights reserved.