Journal
ACS CHEMICAL BIOLOGY
Volume 12, Issue 1, Pages 174-182Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.6b00849
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Funding
- PhRMA Foundation Fellowship in Pharmacology/Toxicology
- National Cancer Institute [R01CA184103]
- Flight Attendant Medical Research Institute
- Prostate Cancer Foundation
- Johns Hopkins Institute for Clinical and Translational Research from the National Center for Advancing Translational Sciences (NCATS) [UL1 TR 001079]
- NIH shared instrumentation grant [S10RR024550]
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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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