Int J Biol Sci 2018; 14(10):1175-1185. doi:10.7150/ijbs.26011

Research Paper

Astemizole Inhibits mTOR Signaling and Angiogenesis by Blocking Cholesterol Trafficking

Junfang Lyu1, Eun Ju Yang1, Sarah A. Head2, Nana Ai1, Baoyuan Zhang1, Changjie Wu1, Ruo-Jing Li2, Yifan Liu1, Harapriya Chakravarty1, Shaolin Zhang1, Kin Yip Tam1, Yongjun Dang3, Ho Jeong Kwon4, Wei Ge1, Jun O. Liu2,5, Joong Sup Shim1✉

1. 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


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.

Keywords: cholesterol trafficking, angiogenesis, astemizole, NPC1, mTOR

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How to cite this article:
Lyu J, Yang EJ, Head SA, Ai N, Zhang B, Wu C, Li RJ, Liu Y, Chakravarty H, Zhang S, Tam KY, Dang Y, Kwon HJ, Ge W, Liu JO, Shim JS. Astemizole Inhibits mTOR Signaling and Angiogenesis by Blocking Cholesterol Trafficking. Int J Biol Sci 2018; 14(10):1175-1185. doi:10.7150/ijbs.26011. Available from