Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells
Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells
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DOI：
10.1073/pnas.1512867112
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发表时间：
2015-12-29
影响因子：
11.1
通讯作者：
Liu, Jun O.
中科院分区：
文献类型：
--
作者：
Head, Sarah A.;Shi, Wei;Liu, Jun O.
伊曲康唑是一种临床常用的抗真菌药物，在唑类抗真菌药物中具有独特的抗血管生成和抗癌活性。先前的机制研究表明，伊曲康唑抑制雷帕霉素（mTOR）信号通路的机制靶点，该信号通路已知是内皮细胞功能和血管生成的关键调节剂。然而，伊曲康唑介导这种活性的分子靶点仍然未知。在这里，我们确定了伊曲康唑在内皮细胞中的主要靶点为线粒体蛋白电压依赖性阴离子通道1（VDAC 1），其通过控制离子和小代谢物通过线粒体外膜来调节线粒体代谢。VDAC 1敲低可显著抑制人脐静脉细胞（HUVEC）中的mTOR活性和细胞增殖，揭示了VDAC 1和mTOR之间先前未知的联系。伊曲康唑抑制VDAC 1会破坏线粒体代谢，导致细胞AMP：ATP比率增加和AMP活化蛋白激酶（AMPK）（mTOR的上游调节因子）活化。VDAC 1敲除细胞对伊曲康唑的AMPK激活和mTOR抑制具有抗性，表明VDAC 1是该活性的介导剂。此外，另一种已知的VDAC靶向化合物erastin也可激活AMPK并抑制mTOR和HUVEC增殖。因此，VDAC 1代表了内皮细胞中mTOR信号传导的新型上游调节因子，也是开发血管生成抑制剂的有希望的靶点。
Itraconazole, a clinically used antifungal drug, was found to possess potent antiangiogenic and anticancer activity that is unique among the azole antifungals. Previous mechanistic studies have shown that itraconazole inhibits the mechanistic target of rapamycin (mTOR) signaling pathway, which is known to be a critical regulator of endothelial cell function and angiogenesis. However, the molecular target of itraconazole that mediates this activity has remained unknown. Here we identify the major target of itraconazole in endothelial cells as the mitochondrial protein voltage-dependent anion channel 1 (VDAC1), which regulates mitochondrial metabolism by controlling the passage of ions and small metabolites through the outer mitochondrial membrane. VDAC1 knockdown profoundly inhibits mTOR activity and cell proliferation in human umbilical vein cells (HUVEC), uncovering a previously unknown connection between VDAC1 and mTOR. Inhibition of VDAC1 by itraconazole disrupts mitochondrial metabolism, leading to an increase in the cellular AMP: ATP ratio and activation of the AMP-activated protein kinase (AMPK), an upstream regulator of mTOR. VDAC1-knockout cells are resistant to AMPK activation and mTOR inhibition by itraconazole, demonstrating that VDAC1 is the mediator of this activity. In addition, another known VDAC-targeting compound, erastin, also activates AMPK and inhibits mTOR and proliferation in HUVEC. VDAC1 thus represents a novel upstream regulator of mTOR signaling in endothelial cells and a promising target for the development of angiogenesis inhibitors.