UM  > 健康科學學院
The antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells
Sarah A. Head1; Wei Shi1,2; Liang Zhao3; Kirill Gorshkov1; Kalyan Pasunooti1,4; Yue Chen5; Zhiyou Deng5; Ruo-jing Li1; Joong Sup Shim1,6; Wenzhi Tan7; Thomas Hartung3; Jin Zhang1; Yingming Zhao5; Marco Colombini7; Jun O. Liu1,8
2015
Source PublicationPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN0027-8424
Volume112Issue:52Pages:E7276-E7285
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.

KeywordAngiogenesis Mitochondria Metabolism Itraconazole Vdac1
DOIhttps://doi.org/10.1073/pnas.1512867112
Indexed BySCI
Language英语
WOS Research AreaScience & Technology - Other Topics
WOS SubjectMultidisciplinary Sciences
WOS IDWOS:000367234700019
全文获取链接
引用统计
被引频次[WOS]:39   [WOS记录]     [WOS相关记录]
Document TypeJournal article
专题Faculty of Health Sciences
Corresponding AuthorJun O. Liu
Affiliation1.Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD, 21205
2.Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR, 72701
3.Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, 21205
4.Division of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University, Singapore, 637551
5.Ben May Department of Cancer Research, The University of Chicago, Chicago, IL, 60637
6.Faculty of Health Sciences, University of Macau, Taipa, Macau Special Administrative Region, China
7.Department of Biology, University of Maryland, College Park, MD, 20742
8.Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, 21205
推荐引用方式
GB/T 7714
Sarah A. Head,Wei Shi,Liang Zhao,et al. The antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2015,112(52):E7276-E7285.
APA Sarah A. Head.,Wei Shi.,Liang Zhao.,Kirill Gorshkov.,Kalyan Pasunooti.,...&Jun O. Liu.(2015).The antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,112(52),E7276-E7285.
MLA Sarah A. Head,et al."The antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 112.52(2015):E7276-E7285.
个性服务
推荐该条目
保存到收藏夹
查看访问统计
导出为Endnote文件
Google Scholar
中相似的文章 Google Scholar
[Sarah A. Head]的文章
[Wei Shi]的文章
[Liang Zhao]的文章
Baidu academic
中相似的文章 Baidu academic
[Sarah A. Head]的文章
[Wei Shi]的文章
[Liang Zhao]的文章
Bing Scholar
中相似的文章 Bing Scholar
[Sarah A. Head]的文章
[Wei Shi]的文章
[Liang Zhao]的文章
相关权益政策
暂无数据
收藏/分享
所有评论 (0)
暂无评论
 

除非特别说明,本系统中所有内容都受版权保护,并保留所有权利。