PUBLICATION
Astemizole Inhibits mTOR Signaling and Angiogenesis by Blocking Cholesterol Trafficking
- Authors
- Lyu, J., Yang, E.J., Head, S.A., Ai, N., Zhang, B., Wu, C., Li, R.J., Liu, Y., Chakravarty, H., Zhang, S., Tam, K.Y., Dang, Y., Kwon, H.J., Ge, W., Liu, J.O., Shim, J.S.
- ID
- ZDB-PUB-180821-5
- Date
- 2018
- Source
- International journal of biological sciences 14: 1175-1185 (Journal)
- Registered Authors
- Ge, Wei
- Keywords
- NPC1, angiogenesis, astemizole, cholesterol trafficking, mTOR
- MeSH Terms
-
- A549 Cells
- Astemizole/therapeutic use*
- Biological Transport/drug effects
- Blotting, Western
- Cell Movement/drug effects
- Cell Proliferation/drug effects
- Cholesterol/metabolism*
- Fluorescent Antibody Technique
- Human Umbilical Vein Endothelial Cells
- Humans
- Neovascularization, Pathologic/drug therapy*
- Niemann-Pick C1 Protein/metabolism
- Signal Transduction/drug effects
- Signal Transduction/genetics
- TOR Serine-Threonine Kinases/genetics
- TOR Serine-Threonine Kinases/metabolism*
- PubMed
- 30123067 Full text @ Int. J. Biol. Sci.
Citation
Lyu, J., Yang, E.J., Head, S.A., Ai, N., Zhang, B., Wu, C., Li, R.J., Liu, Y., Chakravarty, H., Zhang, S., Tam, K.Y., Dang, Y., Kwon, H.J., Ge, W., Liu, J.O., Shim, J.S. (2018) Astemizole Inhibits mTOR Signaling and Angiogenesis by Blocking Cholesterol Trafficking. International journal of biological sciences. 14:1175-1185.
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 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping