Astemizole Inhibits mTOR Signaling and Angiogenesis by Blocking Cholesterol Trafficking

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.

Prediction of Potential Prognostic Tumor Markers of Re-ascites After Chemotherapy for Ovarian Cancer Based on LC/MS Method ​

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ORP2, a cholesterol transporter, regulates angiogenic signaling in endothelial cells

“…Recently, PM cholesterol has proven to play an important role in the regulation of angiogenesis, that is, in the formation of new blood vessels from pre-existing ones. [3][4][5][6] However, the factors and detailed mechanisms linking cholesterol transport to angiogenesis remain poorly understood.…”

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