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Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth
Lyu, Junfang1; Yang, Eun Ju1; Head, Sarah A.2,3; Ai, Nana1; Zhang, Baoyuan1; Wu, Changjie1; Li, Ruo-Jing2,3; Liu, Yifan1; Yang, Chen4; Dang, Yongjun4; Kwon, Ho Jeong5; Ge, Wei1; Liu, Jun O.2,3,6; Shim, Joong Sup1,2,3
2017-11-28
Source PublicationCANCER LETTERS
ISSN0304-3835
Volume409Pages:91-103
Abstract

Cholesterol is an important modulator of membrane protein function and signaling in endothelial cells, thus making it an emerging target for anti-angiogenic agents. In this study, we employed a phenotypic screen that detects intracellular cholesterol distribution in endothelial cells (HUVEC) and identified 13 existing drugs as cholesterol trafficking inhibitors. Cepharanthine, an approved drug for anti-inflammatory and cancer management use, was amongst the candidates, which was selected for indepth mechanistic studies to link cholesterol trafficking and angiogenesis. Cepharanthine inhibited the endolysosomal trafficking of free-cholesterol and low-density lipoprotein in HUVEC by binding to Niemann-Pick disease, type Cl (NPC1) protein and increasing the lysosomal pH. The blockade of cholesterol trafficking led to a cholesterol-dependent dissociation of mTOR from the lysosomes and inhibition of its downstream signaling. Cepharanthine inhibited angiogenesis in HUVEC and in zebrafish in a cholesterol-dependent manner. Furthermore, cepharanthine suppressed tumor growth in vivo by inhibiting angiogenesis and it enhanced the antitumor activity of the standard chemotherapy cisplatin in lung and breast cancer xenografts in mice. Altogether, these results strongly support the idea that cholesterol trafficking is a viable drug target for anti-angiogenesis and that the inhibitors identified among existing drugs, such as cepharanthine, could be potential anti-angiogenic and antitumor agents. (C) 2017 Elsevier B.V. All rights reserved.

KeywordCholesterol Trafficking Angiogenesis Tumor Lysosome Cepharanthine
DOI10.1016/j.canlet.2017.09.009
URLView the original
Indexed BySCI
Language英语
WOS Research AreaOncology
WOS SubjectOncology
WOS IDWOS:000413709400010
PublisherELSEVIER IRELAND LTD
The Source to ArticleWOS
Fulltext Access
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Cited Times [WOS]:10   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorShim, Joong Sup
Affiliation1.Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
2.Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
3.The SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
4.Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
5.Chemical Genomics Global Research Laboratory, Department of Biotechnology, College of Life Science & Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea
6.Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
First Author AffilicationFaculty of Health Sciences
Corresponding Author AffilicationFaculty of Health Sciences
Recommended Citation
GB/T 7714
Lyu, Junfang,Yang, Eun Ju,Head, Sarah A.,et al. Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth[J]. CANCER LETTERS,2017,409:91-103.
APA Lyu, Junfang.,Yang, Eun Ju.,Head, Sarah A..,Ai, Nana.,Zhang, Baoyuan.,...&Shim, Joong Sup.(2017).Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth.CANCER LETTERS,409,91-103.
MLA Lyu, Junfang,et al."Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth".CANCER LETTERS 409(2017):91-103.
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