1 research outputs found
Simultaneous Targeting of NPC1 and VDAC1 by Itraconazole Leads to Synergistic Inhibition of mTOR Signaling and Angiogenesis
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