Simultaneous Targeting of NPC1 and VDAC1 by Itraconazole Leads to Synergistic Inhibition of mTOR Signaling and Angiogenesis.

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 NPC

SUBMITTER: Head SA 

PROVIDER: S-EPMC5791891 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature