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Astemizole Inhibits mTOR Signaling and Angiogenesis by Blocking Cholesterol Trafficking
Lyu, Junfang1; Yang, Eun Ju1; Head, Sarah A.2; Ai, Nana1; Zhang, Baoyuan1; Wu, Changjie1; Li, Ruo-Jing2; Liu, Yifan1; Chakravarty, Harapriya1; Zhang, Shaolin1; Tam, Kin Yip1; Dang, Yongjun3; Kwon, Ho Jeong4; Gel, Wei1; Liu, Jun O.2,5; Shim, Joong Sup1
2018
Source PublicationINTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
ISSN1449-2288
Volume14Issue:10Pages:1175-1185
Abstract

Cholesterol plays a key role in membrane protein function and signaling in endothelial cells. Thus, disturbing cholesterol trafficking is an effective approach for inhibiting angiogenesis. We recently identified astemizole (AST), an antihistamine drug, as a cholesterol trafficking inhibitor from a phenotypic screen. In this study, we found that AST induced cholesterol accumulation in the lysosome by binding to the sterol-sensing domain of Niemann-Pick disease, type Cl (NPC1), a lysosomal surface protein responsible for cholesterol transport. Inhibition of cholesterol trafficking by AST led to the depletion of membrane cholesterol, causing SREBP1 nuclear localization. The depletion of membrane cholesterol resulted in dissociation of mammalian target of rapamycin (mTOR) from the lysosomal surface and inactivation of mTOR signaling. These effects were effectively rescued by addition of exogenous cholesterol. AST inhibited endothelial cell proliferation, migration and tube formation in a cholesterol-dependent manner. Furthermore, AST inhibited zebrafish angiogenesis in a cholesterol-dependent manner. Together, our data suggest that AST is a new class of NPC1 antagonist that inhibits cholesterol trafficking in endothelial cells and angiogenesis.

KeywordCholesterol Trafficking Angiogenesis Astemizole Npc1 Mtor
DOIhttp://doi.org/10.7150/ijbs.26011
URLView the original
Indexed BySCI
Language英语
WOS Research AreaBiochemistry & Molecular Biology ; Life Sciences & Biomedicine - Other Topics
WOS SubjectBiochemistry & Molecular Biology ; Biology
WOS IDWOS:000441909000003
PublisherIVYSPRING INT PUBL
The Source to ArticleWOS
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Cited Times [WOS]:1   [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; The SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
3.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.
4.Chemical Genomics Global Research Laboratory, Department of Biotechnology, College of Life Science & Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
5.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. Astemizole Inhibits mTOR Signaling and Angiogenesis by Blocking Cholesterol Trafficking[J]. INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES,2018,14(10):1175-1185.
APA Lyu, Junfang.,Yang, Eun Ju.,Head, Sarah A..,Ai, Nana.,Zhang, Baoyuan.,...&Shim, Joong Sup.(2018).Astemizole Inhibits mTOR Signaling and Angiogenesis by Blocking Cholesterol Trafficking.INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES,14(10),1175-1185.
MLA Lyu, Junfang,et al."Astemizole Inhibits mTOR Signaling and Angiogenesis by Blocking Cholesterol Trafficking".INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES 14.10(2018):1175-1185.
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