Simultaneous Targeting of NPC1 and VDAC1 by Itraconazole Leads to Synergistic Inhibition of mTOR Signaling and Angiogenesis.
Simultaneous Targeting of NPC1 and VDAC1 by Itraconazole Leads to Synergistic Inhibition of mTOR Signaling and Angiogenesis.
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DOI：
10.1021/acschembio.6b00849
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发表时间：
2017-01-20
影响因子：
4
通讯作者：
Liu JO
中科院分区：
文献类型：
--
作者：
Head SA;Shi WQ;Yang EJ;Nacev BA;Hong SY;Pasunooti KK;Li RJ;Shim JS;Liu JO
抗真菌药物伊曲康唑最近被发现显示出有效的抗血管生成活性，并已被重新用作研究抗癌药物。伊曲康唑通过抑制mTOR信号通路发挥抗血管生成活性，但其分子机制尚不清楚。我们最近发现线粒体蛋白VDAC1是伊曲康唑的靶标，也是其激活AMPK的介质，AMPK是mTOR的上游调节因子。然而，VDAC1不能解释先前报道的伊曲康唑对胆固醇运输的抑制，伊曲康唑也被证明会导致mTOR抑制。在这项研究中，我们证明伊曲康唑抑制胆固醇运输是由于直接抑制溶酶体蛋白NPC1。我们进一步利用诱变、与U18666A竞争和分子对接的方法，将伊曲康唑的结合位点定位到NPC1的甾醇敏感区域。最后，我们证明AMPK激活和胆固醇运输抑制同时导致mTOR、内皮细胞增殖和血管生成的协同抑制。
The antifungal drug itraconazole was recently found to exhibit potent antiangiogenic activity and has since been repurposed as an investigational anticancer agent. Itraconazole has been shown to exert its antiangiogenic activity through inhibition of the mTOR signaling pathway, but the molecular mechanism of action was unknown. We recently identified the mitochondrial protein VDAC1 as a target of itraconazole and a mediator of its activation of AMPK, an upstream regulator of mTOR. However, VDAC1 could not account for the previously reported inhibition of cholesterol trafficking by itraconazole, which was also demonstrated to lead to mTOR inhibition. In this study, we demonstrate that cholesterol trafficking inhibition by itraconazole is due to direct inhibition of the lysosomal protein NPC1. We further map the binding site of itraconazole to the sterol-sensing domain of NPC1 using mutagenesis, competition with U18666A, and molecular docking. Finally, we demonstrate that simultaneous AMPK activation and cholesterol trafficking inhibition leads to synergistic inhibition of mTOR, endothelial cell proliferation, and angiogenesis.
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影响因子：
5.6
作者：
Pópulo H;Lopes JM;Soares P
通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1073/pnas.1512867112
发表时间：
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影响因子：
11.1
作者：
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通讯作者：
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影响因子：
4.4
作者：
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通讯作者：
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