Moschamindole induces glioma cell apoptosis by blocking Mia40-dependent mitochondrial intermembrane space assembly and oxidative respiration
Moschamindole induces glioma cell apoptosis by blocking Mia40-dependent mitochondrial intermembrane space assembly and oxidative respiration
复制标题
Moschamindole 通过阻断 Mia40 依赖性线粒体膜间空间组装和氧化呼吸诱导胶质瘤细胞凋亡
DOI：
10.1002/ptr.7061
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发表时间：
2021-04-15
影响因子：
7.2
通讯作者：
Chen, Lei
中科院分区：
文献类型：
--
作者：
Huang, Guo-Dong;Chen, Fan-Fan;Chen, Lei
多形性胶质母细胞瘤（GBM）是成人中枢神经系统最常见、最致命、最具侵袭性的肿瘤。在这项研究中，我们首次发现，moschamindole（MCD），一种罕见的酚酰胺与8/6/6/5/5环，是一个主要的生物活性成分来自芦苇communis三（禾本科），表现出潜在的细胞毒性作用对TMZ耐药GBM细胞系和异种移植模型。细胞周期阻滞、caspase-3/7激活和膜电位去极化证实了MCD诱导的内在凋亡信号和线粒体功能障碍。此外，探索机制的研究表明，MCD通过PCR测定和免疫印迹分析特异性抑制Mia 40介导的线粒体膜间隙（IMS）蛋白的氧化折叠。MCD依赖其正电荷与线粒体氧化呼吸相关，从而阻断能量代谢并诱导细胞凋亡。Mia 40的过表达和上调被证明可以逆转MCD诱导的细胞凋亡，并分别与体外和体内GBM的化疗耐药性相关。综上所述，我们的研究表明Mia 40是胶质母细胞瘤化疗耐药的潜在靶点，并表明MCD可能是基于线粒体代谢特征和Mia 40表达的化疗耐药GBM个体化治疗的潜在药物。
Glioblastoma multiforme (GBM) is the most frequent, lethal, and aggressive tumor of the central nervous system in adults. In this study, we found for the first time that moschamindole (MCD), a rare phenolic amide with 8/6/6/5/5 rings, is a major bioactive constituent derived from Phragmites communis Trin (Poaceae) that exhibits a potential cytotoxic effect on both TMZ-resistant GBM cell lines and xenograft models. MCD-induced intrinsic apoptosis signals and mitochondrial dysfunction were confirmed by cell cycle arrest, caspase-3/7 activation, and membrane potential depolarization. Furthermore, investigations exploring the mechanism showed that MCD specifically inhibits Mia40-mediated oxidative folding of mitochondrial intermembrane space (IMS) proteins via PCR assay and immunoblot analysis. MCD relies on its positive charge to associate with mitochondrial oxidative respiration, thus blocking energy metabolism and inducing apoptosis. Overexpression and upregulation of Mia40 were proven to reverse MCD-induced apoptosis and were correlated with the chemoresistance of GBM in vitro and in vivo, respectively. Taken together, our study demonstrates that Mia40 is a potential target of the chemoresistance of glioblastoma and suggests that MCD might be a potential agent for the individualized treatment of chemoresistant GBM based on mitochondrial metabolic characteristics and Mia40 expression.