Ym155 localizes to the mitochondria leading to mitochondria dysfunction and activation of AMPK that inhibits BMP signaling in lung cancer cells.
Ym155 localizes to the mitochondria leading to mitochondria dysfunction and activation of AMPK that inhibits BMP signaling in lung cancer cells.
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DOI：
10.1038/s41598-022-17446-y
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发表时间：
2022-07-30
影响因子：
4.6
通讯作者：
Langenfeld, John
中科院分区：
文献类型：
--
作者：
Mondal, Arindam;Jia, Dongxuan;Bhatt, Vrushank;Akel, Moumen;Roberge, Jacques;Guo, Jessie Yanxiang;Langenfeld, John
咪唑鎓化合物 Ym155 首次被报道为生存素抑制剂。在临床前研究中，Ym155 可有效诱导多种类型癌细胞的细胞死亡。然而，在II期临床试验中，Ym155未能表现出显着的益处。研究表明，Ym155 在癌细胞中的细胞毒性作用不是由生存素的抑制介导的。了解 Ym155 诱导细胞死亡的机制将为如何提高其癌症治疗功效提供重要见解。我们证明了 Ym155 通过定位于线粒体导致线粒体功能障碍而诱导细胞死亡的新机制。我们的研究表明，Ym155 结合线粒体 DNA，导致氧化磷酸化减少、TCA 循环中间体减少以及线粒体通透性增加。此外，我们发现 Ym155 和其他线粒体抑制剂诱导的线粒体应激会激活 AMP 激活激酶，导致骨形态发生蛋白 (BMP) 信号传导下调。我们提供了第一个证据表明 Ym155 通过破坏线粒体功能来启动细胞死亡。
The imidazolium compound Ym155 was first reported to be a survivin inhibitor. Ym155 potently induces cell death of many types of cancer cells in preclinical studies. However, in phase II clinical trials Ym155 failed to demonstrate a significant benefit. Studies have suggested that the cytotoxic effects of Ym155 in cancer cells are not mediated by the inhibition of survivin. Understanding the mechanism by which Ym155 induces cell death would provide important insight how to improve its efficacy as a cancer therapeutic. We demonstrate a novel mechanism by which Ym155 induces cell death by localizing to the mitochondria causing mitochondrial dysfunction. Our studies suggest that Ym155 binds mitochondrial DNA leading to a decrease in oxidative phosphorylation, decrease in TCA cycle intermediates, and an increase in mitochondrial permeability. Furthermore, we show that mitochondrial stress induced by Ym155 and other mitochondrial inhibitors activates AMP-activated kinase leading to the downregulation to bone morphogenetic protein (BMP) signaling. We provide first evidence that Ym155 initiates cell death by disrupting mitochondrial function.
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影响因子：
12.8
作者：
Jeon SM
通讯作者：
Jeon SM
DOI：
10.1186/1478-811x-8-31
发表时间：
2010-12-22
期刊：
Cell communication and signaling : CCS
影响因子：
--
作者：
Chaitanya GV;Steven AJ;Babu PP
通讯作者：
Babu PP
DOI：
10.1042/bj20100814
发表时间：
2010-09-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Altieri DC
通讯作者：
Altieri DC
影响因子：
10.5
作者：
Guo, Jessie Yanxiang;Chen, Hsin-Yi;White, Eileen
通讯作者：
White, Eileen
影响因子：
37.3
作者：
Augeri DJ;Langenfeld E;Castle M;Gilleran JA;Langenfeld J
通讯作者：
Langenfeld J