Astemizole inhibits mTOR signaling and angiogenesis by blocking cholesterol trafficking

Junfang Lyu, Eun Ju Yang, Sarah A. Head, Nana Ai, Baoyuan Zhang, Changjie Wu, Ruo Jing Li, Yifan Liu, Harapriya Chakravarty, Shaolin Zhang, Kin Yip Tam, Yongjun Dang, Ho Jeong Kwon, Wei Ge, Jun O. Liu, Joong Sup Shim

Research output: Contribution to journalArticle


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.

Original languageEnglish
Pages (from-to)1175-1185
Number of pages11
JournalInternational Journal of Biological Sciences
Issue number10
Publication statusPublished - 2018 Jun 23

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Applied Microbiology and Biotechnology
  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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  • Cite this

    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(10), 1175-1185.