Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth

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

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Cholesterol is an important modulator of membrane protein function and signaling in endothelial cells, thus making it an emerging target for anti-angiogenic agents. In this study, we employed a phenotypic screen that detects intracellular cholesterol distribution in endothelial cells (HUVEC) and identified 13 existing drugs as cholesterol trafficking inhibitors. Cepharanthine, an approved drug for anti-inflammatory and cancer management use, was amongst the candidates, which was selected for in-depth mechanistic studies to link cholesterol trafficking and angiogenesis. Cepharanthine inhibited the endolysosomal trafficking of free-cholesterol and low-density lipoprotein in HUVEC by binding to Niemann-Pick disease, type C1 (NPC1) protein and increasing the lysosomal pH. The blockade of cholesterol trafficking led to a cholesterol-dependent dissociation of mTOR from the lysosomes and inhibition of its downstream signaling. Cepharanthine inhibited angiogenesis in HUVEC and in zebrafish in a cholesterol-dependent manner. Furthermore, cepharanthine suppressed tumor growth in vivo by inhibiting angiogenesis and it enhanced the antitumor activity of the standard chemotherapy cisplatin in lung and breast cancer xenografts in mice. Altogether, these results strongly support the idea that cholesterol trafficking is a viable drug target for anti-angiogenesis and that the inhibitors identified among existing drugs, such as cepharanthine, could be potential anti-angiogenic and antitumor agents.

Original languageEnglish
Pages (from-to)91-103
Number of pages13
JournalCancer Letters
Volume409
DOIs
Publication statusPublished - 2017 Nov 28

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Endothelial Cells
Cholesterol
Pharmacology
Growth
Neoplasms
Pharmaceutical Preparations
Type C Niemann-Pick Disease
Anticholesteremic Agents
Angiogenesis Inhibitors
Zebrafish
Lysosomes
cepharanthine
Heterografts
Antineoplastic Agents
LDL Cholesterol
Cisplatin
Lung Neoplasms
Membrane Proteins
Anti-Inflammatory Agents
Breast Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Lyu, Junfang ; Yang, Eun Ju ; Head, Sarah A. ; Ai, Nana ; Zhang, Baoyuan ; Wu, Changjie ; Li, Ruo Jing ; Liu, Yifan ; Yang, Chen ; Dang, Yongjun ; Kwon, Ho Jeong ; Ge, Wei ; Liu, Jun O. ; Shim, Joong Sup. / Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth. In: Cancer Letters. 2017 ; Vol. 409. pp. 91-103.
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abstract = "Cholesterol is an important modulator of membrane protein function and signaling in endothelial cells, thus making it an emerging target for anti-angiogenic agents. In this study, we employed a phenotypic screen that detects intracellular cholesterol distribution in endothelial cells (HUVEC) and identified 13 existing drugs as cholesterol trafficking inhibitors. Cepharanthine, an approved drug for anti-inflammatory and cancer management use, was amongst the candidates, which was selected for in-depth mechanistic studies to link cholesterol trafficking and angiogenesis. Cepharanthine inhibited the endolysosomal trafficking of free-cholesterol and low-density lipoprotein in HUVEC by binding to Niemann-Pick disease, type C1 (NPC1) protein and increasing the lysosomal pH. The blockade of cholesterol trafficking led to a cholesterol-dependent dissociation of mTOR from the lysosomes and inhibition of its downstream signaling. Cepharanthine inhibited angiogenesis in HUVEC and in zebrafish in a cholesterol-dependent manner. Furthermore, cepharanthine suppressed tumor growth in vivo by inhibiting angiogenesis and it enhanced the antitumor activity of the standard chemotherapy cisplatin in lung and breast cancer xenografts in mice. Altogether, these results strongly support the idea that cholesterol trafficking is a viable drug target for anti-angiogenesis and that the inhibitors identified among existing drugs, such as cepharanthine, could be potential anti-angiogenic and antitumor agents.",
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Lyu, J, Yang, EJ, Head, SA, Ai, N, Zhang, B, Wu, C, Li, RJ, Liu, Y, Yang, C, Dang, Y, Kwon, HJ, Ge, W, Liu, JO & Shim, JS 2017, 'Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth', Cancer Letters, vol. 409, pp. 91-103. https://doi.org/10.1016/j.canlet.2017.09.009

Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth. / Lyu, Junfang; Yang, Eun Ju; Head, Sarah A.; Ai, Nana; Zhang, Baoyuan; Wu, Changjie; Li, Ruo Jing; Liu, Yifan; Yang, Chen; Dang, Yongjun; Kwon, Ho Jeong; Ge, Wei; Liu, Jun O.; Shim, Joong Sup.

In: Cancer Letters, Vol. 409, 28.11.2017, p. 91-103.

Research output: Contribution to journalArticle

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T1 - Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth

AU - Lyu, Junfang

AU - Yang, Eun Ju

AU - Head, Sarah A.

AU - Ai, Nana

AU - Zhang, Baoyuan

AU - Wu, Changjie

AU - Li, Ruo Jing

AU - Liu, Yifan

AU - Yang, Chen

AU - Dang, Yongjun

AU - Kwon, Ho Jeong

AU - Ge, Wei

AU - Liu, Jun O.

AU - Shim, Joong Sup

PY - 2017/11/28

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AB - Cholesterol is an important modulator of membrane protein function and signaling in endothelial cells, thus making it an emerging target for anti-angiogenic agents. In this study, we employed a phenotypic screen that detects intracellular cholesterol distribution in endothelial cells (HUVEC) and identified 13 existing drugs as cholesterol trafficking inhibitors. Cepharanthine, an approved drug for anti-inflammatory and cancer management use, was amongst the candidates, which was selected for in-depth mechanistic studies to link cholesterol trafficking and angiogenesis. Cepharanthine inhibited the endolysosomal trafficking of free-cholesterol and low-density lipoprotein in HUVEC by binding to Niemann-Pick disease, type C1 (NPC1) protein and increasing the lysosomal pH. The blockade of cholesterol trafficking led to a cholesterol-dependent dissociation of mTOR from the lysosomes and inhibition of its downstream signaling. Cepharanthine inhibited angiogenesis in HUVEC and in zebrafish in a cholesterol-dependent manner. Furthermore, cepharanthine suppressed tumor growth in vivo by inhibiting angiogenesis and it enhanced the antitumor activity of the standard chemotherapy cisplatin in lung and breast cancer xenografts in mice. Altogether, these results strongly support the idea that cholesterol trafficking is a viable drug target for anti-angiogenesis and that the inhibitors identified among existing drugs, such as cepharanthine, could be potential anti-angiogenic and antitumor agents.

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