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Simultaneous Targeting of NPC1 and VDAC1 by Itraconazole Leads to Synergistic Inhibition of mTOR Signaling and Angiogenesis
Head, Sarah A.1,2; Shi, Wei Q.1,3; Yang, Eun Ju4; Nacev, Benjamin A.1,5; Hong, Sam Y.1,2; Pasunooti, Kalyan K.1,6; Li, Ruo-Jing1,2; Shim, Joong Sup1,4; Liu, Jun O.1,2,7
2017-01
Source PublicationACS CHEMICAL BIOLOGY
ISSN1554-8929
Volume12Issue:1Pages:174-182
Abstract

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.

DOI10.1021/acschembio.6b00849
URLView the original
Indexed BySCI
Language英语
WOS Research AreaBiochemistry & Molecular Biology
WOS SubjectBiochemistry & Molecular Biology
WOS IDWOS:000392569400019
PublisherAMER CHEMICAL SOC
The Source to ArticleWOS
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Cited Times [WOS]:33   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Affiliation1.Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States
2.SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States
3.Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, Arkansas 72701, United States
4.Faculty of Health Sciences, University of Macau, Taipa, Macau SAR China
5.Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States
6.Division of Structural Biology & Biochemistry, School of Biological Sciences, Nanyang Technological University, Singapore
7.Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States
Recommended Citation
GB/T 7714
Head, Sarah A.,Shi, Wei Q.,Yang, Eun Ju,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):174-182.
APA Head, Sarah A..,Shi, Wei Q..,Yang, Eun Ju.,Nacev, Benjamin A..,Hong, Sam Y..,...&Liu, Jun O..(2017).Simultaneous Targeting of NPC1 and VDAC1 by Itraconazole Leads to Synergistic Inhibition of mTOR Signaling and Angiogenesis.ACS CHEMICAL BIOLOGY,12(1),174-182.
MLA Head, Sarah 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):174-182.
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