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Simultaneous targeting of NPC1 and VDAC1 by itraconazole leads to synergistic inhibition of MTOR signaling and angiogenesis
Head S.A.; Shi W.Q.; Yang E.J.; Nacev B.A.; Hong S.Y.; Pasunooti K.K.; Li R.-J.; Shim J.S.; Liu J.O.
2017
Source PublicationACS Chemical Biology
ISSN15548929
Volume12Issue:1Pages:174
AbstractThe 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. © 2016 American Chemical Society.
DOI10.1021/acschembio.6b00849
URLView the original
Language英语
The Source to ArticleScopus
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Cited Times [WOS]:17   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionUniversity of Macau
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Head S.A.,Shi W.Q.,Yang E.J.,et al. Simultaneous targeting of NPC1 and VDAC1 by itraconazole leads to synergistic inhibition of MTOR signaling and angiogenesis[J]. ACS Chemical Biology,2017,12(1):174.
APA Head S.A..,Shi W.Q..,Yang E.J..,Nacev B.A..,Hong S.Y..,...&Liu J.O..(2017).Simultaneous targeting of NPC1 and VDAC1 by itraconazole leads to synergistic inhibition of MTOR signaling and angiogenesis.ACS Chemical Biology,12(1),174.
MLA Head S.A.,et al."Simultaneous targeting of NPC1 and VDAC1 by itraconazole leads to synergistic inhibition of MTOR signaling and angiogenesis".ACS Chemical Biology 12.1(2017):174.
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