Although the evidence is still limited, a growing body of research suggests music may have beneficial effects for diseases such as Parkinson’s.
Image credit: Shutterstock/agsandrew.
New Research In
Physical Sciences
Featured Portals
Articles by Topic
Biological Sciences
Featured Portals
Articles by Topic
Edited by Michael N. Hall, University of Basel, Basel, Switzerland, and approved November 12, 2015 (received for review July 7, 2015)
Significance
Tumors promote angiogenesis to facilitate their growth and metastasis; thus, inhibition of angiogenesis is a promising strategy for treating cancer. During angiogenesis, endothelial cells (EC) are stimulated by proangiogenic factors to proliferate and migrate, leading to the formation of new blood vessels. Understanding the mechanisms regulating EC function therefore is essential for the development of new antiangiogenic interventions. Here, we identify a novel mechanism of EC regulation by the recently discovered angiogenesis inhibitor itraconazole, mediated by direct binding to the mitochondrial protein voltage-dependent anion channel 1 (VDAC1). VDAC1 inhibition perturbs mitochondrial ATP production, leading to activation of the AMP-activated protein kinase pathway and subsequent inhibition of mechanistic target of rapamycin, a regulator of EC proliferation. This study suggests VDAC1 may serve as a new therapeutic target for angiogenesis inhibition.
Abstract
Itraconazole, a clinically used antifungal drug, was found to possess potent antiangiogenic and anticancer activity that is unique among the azole antifungals. Previous mechanistic studies have shown that itraconazole inhibits the mechanistic target of rapamycin (mTOR) signaling pathway, which is known to be a critical regulator of endothelial cell function and angiogenesis. However, the molecular target of itraconazole that mediates this activity has remained unknown. Here we identify the major target of itraconazole in endothelial cells as the mitochondrial protein voltage-dependent anion channel 1 (VDAC1), which regulates mitochondrial metabolism by controlling the passage of ions and small metabolites through the outer mitochondrial membrane. VDAC1 knockdown profoundly inhibits mTOR activity and cell proliferation in human umbilical vein cells (HUVEC), uncovering a previously unknown connection between VDAC1 and mTOR. Inhibition of VDAC1 by itraconazole disrupts mitochondrial metabolism, leading to an increase in the cellular AMP:ATP ratio and activation of the AMP-activated protein kinase (AMPK), an upstream regulator of mTOR. VDAC1-knockout cells are resistant to AMPK activation and mTOR inhibition by itraconazole, demonstrating that VDAC1 is the mediator of this activity. In addition, another known VDAC-targeting compound, erastin, also activates AMPK and inhibits mTOR and proliferation in HUVEC. VDAC1 thus represents a novel upstream regulator of mTOR signaling in endothelial cells and a promising target for the development of angiogenesis inhibitors.
Footnotes
- ↵1To whom correspondence should be addressed. Email: joliu{at}jhu.edu.
Author contributions: S.A.H., J.S.S., and J.O.L. designed research; S.A.H., W.S., L.Z., K.G., K.P., Z.D., R.-j.L., and W.T. performed research; T.H., J.Z., Y.Z., and M.C. contributed new reagents/analytic tools; S.A.H., W.S., L.Z., K.G., K.P., Y.C., Z.D., R.-j.L., J.S.S., Y.Z., M.C., and J.O.L. analyzed data; and S.A.H., W.S., and J.O.L. wrote the paper.
Conflict of interest statement: The intellectual properties covering the use of itraconazole and its stereoisomers as angiogenesis inhibitors have been patented by the Johns Hopkins University and licensed to Accelas Pharmaceuticals, Inc., of which J.O.L. is a cofounder and equity holder. The potential conflict of interest has been managed by the Office of Policy Coordination of the Johns Hopkins School of Medicine. The results disclosed in this article are not directly related to those intellectual properties.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1512867112/-/DCSupplemental.
http://www.pnas.org/preview_site/misc/userlicense.xhtml
Itraconazole targets VDAC1 to modulate AMPK/mTOR
Sign up for Article Alerts
Jump to section
You May Also be Interested in
Astronomers thought they’d finally figured out where gold and other heavy elements in the universe came from. In light of recent results, they’re not so sure.
Image credit: Science Source/Tom McHugh.
Researchers are still trying to understand what causes this strong correlation between neural and social networks.
Image credit: Shutterstock/Yeongsik Im.
Aleix Martinez explains why facial expressions often are not accurate indicators of emotion.
CRISPR-Cas9 gene editing can improve the effectiveness of spermatogonial stem cell transplantation in mice and livestock, a study finds.
Image credit: Jon M. Oatley.