State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, China.
Basic Clin Pharmacol Toxicol. 2013 Sep;113(3):145-51. doi: 10.1111/bcpt.12074. Epub 2013 May 20.
Small molecule S1 is a pan-BH3 mimetic that can bind antiapoptotic Bcl-2, Bcl-xL and Mcl-1 proteins. Herein, different Bcl-2 member expression cancer cell lines (NCI-H345, MCF-7, SMMC-7721 and Hela) and cells deficient in Bax and/or Bak by shRNA were used to unravel the cascade of events by which S1 promotes apoptosis compared with Bcl-2/Bcl-xL inhibitor ABT-737. We identified that S1 exhibited broader antitumour spectrum than ABT-737 through disruption of more Bcl-2 interactions including Mcl-1/Bak interaction. Moreover, the individual and combined roles of Bax and Bak in S1-induced apoptosis were revealed. Our results showed that S1 induced a Bak-mediated apoptosis. Bak played a predominant role in either S1 or ABT-737-induced apoptosis through the cooperation with Bax on the formation of large oligomers on mitochondrial membrane.
小分子 S1 是一种泛 BH3 模拟物，可与抗凋亡的 Bcl-2、Bcl-xL 和 Mcl-1 蛋白结合。在此，我们使用不同的 Bcl-2 成员表达的癌细胞系（NCI-H345、MCF-7、SMMC-7721 和 Hela）和 Bax 和/或 Bak 敲低的细胞，揭示 S1 与 Bcl-2/Bcl-xL 抑制剂 ABT-737 相比促进细胞凋亡的级联事件。我们发现，S1 通过破坏包括 Mcl-1/Bak 相互作用在内的更多 Bcl-2 相互作用，表现出比 ABT-737 更广泛的抗肿瘤谱。此外，还揭示了 Bax 和 Bak 在 S1 诱导的细胞凋亡中的单独和联合作用。我们的结果表明，S1 诱导了 Bak 介导的细胞凋亡。Bak 通过与 Bax 合作在线粒体膜上形成大寡聚体，在 S1 或 ABT-737 诱导的细胞凋亡中发挥主要作用。
