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Astemizole Inhibits mTOR Signaling and Angiogenesis by Blocking Cholesterol Trafficking
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 p...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097475/ https://www.ncbi.nlm.nih.gov/pubmed/30123067 http://dx.doi.org/10.7150/ijbs.26011 |
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author | Lyu, Junfang Yang, Eun Ju Head, Sarah A. Ai, Nana Zhang, Baoyuan Wu, Changjie Li, Ruo-Jing Liu, Yifan Chakravarty, Harapriya Zhang, Shaolin Tam, Kin Yip Dang, Yongjun Kwon, Ho Jeong Ge, Wei Liu, Jun O. Shim, Joong Sup |
author_facet | Lyu, Junfang Yang, Eun Ju Head, Sarah A. Ai, Nana Zhang, Baoyuan Wu, Changjie Li, Ruo-Jing Liu, Yifan Chakravarty, Harapriya Zhang, Shaolin Tam, Kin Yip Dang, Yongjun Kwon, Ho Jeong Ge, Wei Liu, Jun O. Shim, Joong Sup |
author_sort | Lyu, Junfang |
collection | PubMed |
description | 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 C1 (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. |
format | Online Article Text |
id | pubmed-6097475 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-60974752018-08-17 Astemizole Inhibits mTOR Signaling and Angiogenesis by Blocking Cholesterol Trafficking Lyu, Junfang Yang, Eun Ju Head, Sarah A. Ai, Nana Zhang, Baoyuan Wu, Changjie Li, Ruo-Jing Liu, Yifan Chakravarty, Harapriya Zhang, Shaolin Tam, Kin Yip Dang, Yongjun Kwon, Ho Jeong Ge, Wei Liu, Jun O. Shim, Joong Sup Int J Biol Sci Research Paper 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 C1 (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. Ivyspring International Publisher 2018-06-23 /pmc/articles/PMC6097475/ /pubmed/30123067 http://dx.doi.org/10.7150/ijbs.26011 Text en © Ivyspring International Publisher This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions. |
spellingShingle | Research Paper Lyu, Junfang Yang, Eun Ju Head, Sarah A. Ai, Nana Zhang, Baoyuan Wu, Changjie Li, Ruo-Jing Liu, Yifan Chakravarty, Harapriya Zhang, Shaolin Tam, Kin Yip Dang, Yongjun Kwon, Ho Jeong Ge, Wei Liu, Jun O. Shim, Joong Sup Astemizole Inhibits mTOR Signaling and Angiogenesis by Blocking Cholesterol Trafficking |
title | Astemizole Inhibits mTOR Signaling and Angiogenesis by Blocking Cholesterol Trafficking |
title_full | Astemizole Inhibits mTOR Signaling and Angiogenesis by Blocking Cholesterol Trafficking |
title_fullStr | Astemizole Inhibits mTOR Signaling and Angiogenesis by Blocking Cholesterol Trafficking |
title_full_unstemmed | Astemizole Inhibits mTOR Signaling and Angiogenesis by Blocking Cholesterol Trafficking |
title_short | Astemizole Inhibits mTOR Signaling and Angiogenesis by Blocking Cholesterol Trafficking |
title_sort | astemizole inhibits mtor signaling and angiogenesis by blocking cholesterol trafficking |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097475/ https://www.ncbi.nlm.nih.gov/pubmed/30123067 http://dx.doi.org/10.7150/ijbs.26011 |
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