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Research Article

Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells

Sarah A. Head, Wei Shi, Liang Zhao, Kirill Gorshkov, Kalyan Pasunooti, Yue Chen, Zhiyou Deng, Ruo-jing Li, Joong Sup Shim, Wenzhi Tan, Thomas Hartung, Jin Zhang, Yingming Zhao, Marco Colombini, and Jun O. Liu
PNAS first published December 10, 2015; https://doi.org/10.1073/pnas.1512867112
Sarah A. Head
aDepartment of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205;
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Wei Shi
aDepartment of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205;
bDepartment of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701;
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Liang Zhao
cDepartment of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205;
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Kirill Gorshkov
aDepartment of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205;
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Kalyan Pasunooti
aDepartment of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205;
dDivision of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University, Singapore 637551;
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Yue Chen
eBen May Department of Cancer Research, The University of Chicago, Chicago, IL 60637;
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Zhiyou Deng
eBen May Department of Cancer Research, The University of Chicago, Chicago, IL 60637;
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Ruo-jing Li
aDepartment of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205;
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Joong Sup Shim
aDepartment of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205;
fFaculty of Health Sciences, University of Macau, Taipa, Macau Special Administrative Region, China;
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Wenzhi Tan
gDepartment of Biology, University of Maryland, College Park, MD 20742;
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Thomas Hartung
cDepartment of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205;
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Jin Zhang
aDepartment of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205;
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Yingming Zhao
eBen May Department of Cancer Research, The University of Chicago, Chicago, IL 60637;
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Marco Colombini
gDepartment of Biology, University of Maryland, College Park, MD 20742;
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Jun O. Liu
aDepartment of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205;
hDepartment of Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21205
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  • For correspondence: joliu@jhu.edu
  1. Edited by Michael N. Hall, University of Basel, Basel, Switzerland, and approved November 12, 2015 (received for review July 7, 2015)

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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.

  • angiogenesis
  • mitochondria
  • metabolism
  • itraconazole
  • VDAC1

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.

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Itraconazole targets VDAC1 to modulate AMPK/mTOR
Sarah A. Head, Wei Shi, Liang Zhao, Kirill Gorshkov, Kalyan Pasunooti, Yue Chen, Zhiyou Deng, Ruo-jing Li, Joong Sup Shim, Wenzhi Tan, Thomas Hartung, Jin Zhang, Yingming Zhao, Marco Colombini, Jun O. Liu
Proceedings of the National Academy of Sciences Dec 2015, 201512867; DOI: 10.1073/pnas.1512867112

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Itraconazole targets VDAC1 to modulate AMPK/mTOR
Sarah A. Head, Wei Shi, Liang Zhao, Kirill Gorshkov, Kalyan Pasunooti, Yue Chen, Zhiyou Deng, Ruo-jing Li, Joong Sup Shim, Wenzhi Tan, Thomas Hartung, Jin Zhang, Yingming Zhao, Marco Colombini, Jun O. Liu
Proceedings of the National Academy of Sciences Dec 2015, 201512867; DOI: 10.1073/pnas.1512867112
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