Inhibition of angiogenesis by selective estrogen receptor modulators through blockade of cholesterol trafficking rather than estrogen receptor antagonism

Joong Sup Shim, Ruo Jing Li, Junfang Lv, Sarah A. Head, Eun Ju Yang, Jun Liu

Research output: Contribution to journalArticle

Abstract

Selective estrogen receptor modulators (SERM) including tamoxifen are known to inhibit angiogenesis. However, the underlying mechanism, which is independent of their action on the estrogen receptor (ER), has remained largely unknown. In the present study, we found that tamoxifen and other SERM inhibited cholesterol trafficking in endothelial cells, causing a hyper-accumulation of cholesterol in late endosomes/lysosomes. Inhibition of cholesterol trafficking by tamoxifen was accompanied by abnormal subcellular distribution of vascular endothelial growth factor receptor-2 (VEGFR2) and inhibition of the terminal glycosylation of the receptor. Tamoxifen also caused perinuclear positioning of lysosomes, which in turn trapped the mammalian target of rapamycin (mTOR) in the perinuclear region of endothelial cells. Abnormal distribution of VEGFR2 and mTOR and inhibition of VEGFR2 and mTOR activities by tamoxifen were significantly reversed by addition of cholesterol-cyclodextrin complex to the culture media of endothelial cells. Moreover, high concentrations of tamoxifen inhibited endothelial and breast cancer cell proliferation in a cholesterol-dependent, but ER-independent, manner. Together, these results unraveled a previously unrecognized mechanism of angiogenesis inhibition by tamoxifen and other SERM, implicating cholesterol trafficking as an attractive therapeutic target for cancer treatment.

Original languageEnglish (US)
Pages (from-to)106-115
Number of pages10
JournalCancer Letters
Volume362
Issue number1
DOIs
StatePublished - 2015

Fingerprint

Selective Estrogen Receptor Modulators
Tamoxifen
Estrogen Receptors
Cholesterol
Vascular Endothelial Growth Factor Receptor-2
Sirolimus
Endothelial Cells
Lysosomes
Endosomes
Cyclodextrins
Glycosylation
Culture Media
Cell Proliferation
Breast Neoplasms

Keywords

  • Angiogenesis
  • Cholesterol trafficking
  • Selective estrogen receptor modulator
  • Tamoxifen

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Inhibition of angiogenesis by selective estrogen receptor modulators through blockade of cholesterol trafficking rather than estrogen receptor antagonism. / Shim, Joong Sup; Li, Ruo Jing; Lv, Junfang; Head, Sarah A.; Yang, Eun Ju; Liu, Jun.

In: Cancer Letters, Vol. 362, No. 1, 2015, p. 106-115.

Research output: Contribution to journalArticle

Shim, Joong Sup ; Li, Ruo Jing ; Lv, Junfang ; Head, Sarah A. ; Yang, Eun Ju ; Liu, Jun. / Inhibition of angiogenesis by selective estrogen receptor modulators through blockade of cholesterol trafficking rather than estrogen receptor antagonism. In: Cancer Letters. 2015 ; Vol. 362, No. 1. pp. 106-115.
@article{d338c759f28e42a4a1fb7dc6f3b7d3fb,
title = "Inhibition of angiogenesis by selective estrogen receptor modulators through blockade of cholesterol trafficking rather than estrogen receptor antagonism",
abstract = "Selective estrogen receptor modulators (SERM) including tamoxifen are known to inhibit angiogenesis. However, the underlying mechanism, which is independent of their action on the estrogen receptor (ER), has remained largely unknown. In the present study, we found that tamoxifen and other SERM inhibited cholesterol trafficking in endothelial cells, causing a hyper-accumulation of cholesterol in late endosomes/lysosomes. Inhibition of cholesterol trafficking by tamoxifen was accompanied by abnormal subcellular distribution of vascular endothelial growth factor receptor-2 (VEGFR2) and inhibition of the terminal glycosylation of the receptor. Tamoxifen also caused perinuclear positioning of lysosomes, which in turn trapped the mammalian target of rapamycin (mTOR) in the perinuclear region of endothelial cells. Abnormal distribution of VEGFR2 and mTOR and inhibition of VEGFR2 and mTOR activities by tamoxifen were significantly reversed by addition of cholesterol-cyclodextrin complex to the culture media of endothelial cells. Moreover, high concentrations of tamoxifen inhibited endothelial and breast cancer cell proliferation in a cholesterol-dependent, but ER-independent, manner. Together, these results unraveled a previously unrecognized mechanism of angiogenesis inhibition by tamoxifen and other SERM, implicating cholesterol trafficking as an attractive therapeutic target for cancer treatment.",
keywords = "Angiogenesis, Cholesterol trafficking, Selective estrogen receptor modulator, Tamoxifen",
author = "Shim, {Joong Sup} and Li, {Ruo Jing} and Junfang Lv and Head, {Sarah A.} and Yang, {Eun Ju} and Jun Liu",
year = "2015",
doi = "10.1016/j.canlet.2015.03.022",
language = "English (US)",
volume = "362",
pages = "106--115",
journal = "Cancer Letters",
issn = "0304-3835",
publisher = "Elsevier Ireland Ltd",
number = "1",

}

TY - JOUR

T1 - Inhibition of angiogenesis by selective estrogen receptor modulators through blockade of cholesterol trafficking rather than estrogen receptor antagonism

AU - Shim, Joong Sup

AU - Li, Ruo Jing

AU - Lv, Junfang

AU - Head, Sarah A.

AU - Yang, Eun Ju

AU - Liu, Jun

PY - 2015

Y1 - 2015

N2 - Selective estrogen receptor modulators (SERM) including tamoxifen are known to inhibit angiogenesis. However, the underlying mechanism, which is independent of their action on the estrogen receptor (ER), has remained largely unknown. In the present study, we found that tamoxifen and other SERM inhibited cholesterol trafficking in endothelial cells, causing a hyper-accumulation of cholesterol in late endosomes/lysosomes. Inhibition of cholesterol trafficking by tamoxifen was accompanied by abnormal subcellular distribution of vascular endothelial growth factor receptor-2 (VEGFR2) and inhibition of the terminal glycosylation of the receptor. Tamoxifen also caused perinuclear positioning of lysosomes, which in turn trapped the mammalian target of rapamycin (mTOR) in the perinuclear region of endothelial cells. Abnormal distribution of VEGFR2 and mTOR and inhibition of VEGFR2 and mTOR activities by tamoxifen were significantly reversed by addition of cholesterol-cyclodextrin complex to the culture media of endothelial cells. Moreover, high concentrations of tamoxifen inhibited endothelial and breast cancer cell proliferation in a cholesterol-dependent, but ER-independent, manner. Together, these results unraveled a previously unrecognized mechanism of angiogenesis inhibition by tamoxifen and other SERM, implicating cholesterol trafficking as an attractive therapeutic target for cancer treatment.

AB - Selective estrogen receptor modulators (SERM) including tamoxifen are known to inhibit angiogenesis. However, the underlying mechanism, which is independent of their action on the estrogen receptor (ER), has remained largely unknown. In the present study, we found that tamoxifen and other SERM inhibited cholesterol trafficking in endothelial cells, causing a hyper-accumulation of cholesterol in late endosomes/lysosomes. Inhibition of cholesterol trafficking by tamoxifen was accompanied by abnormal subcellular distribution of vascular endothelial growth factor receptor-2 (VEGFR2) and inhibition of the terminal glycosylation of the receptor. Tamoxifen also caused perinuclear positioning of lysosomes, which in turn trapped the mammalian target of rapamycin (mTOR) in the perinuclear region of endothelial cells. Abnormal distribution of VEGFR2 and mTOR and inhibition of VEGFR2 and mTOR activities by tamoxifen were significantly reversed by addition of cholesterol-cyclodextrin complex to the culture media of endothelial cells. Moreover, high concentrations of tamoxifen inhibited endothelial and breast cancer cell proliferation in a cholesterol-dependent, but ER-independent, manner. Together, these results unraveled a previously unrecognized mechanism of angiogenesis inhibition by tamoxifen and other SERM, implicating cholesterol trafficking as an attractive therapeutic target for cancer treatment.

KW - Angiogenesis

KW - Cholesterol trafficking

KW - Selective estrogen receptor modulator

KW - Tamoxifen

UR - http://www.scopus.com/inward/record.url?scp=84933179849&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84933179849&partnerID=8YFLogxK

U2 - 10.1016/j.canlet.2015.03.022

DO - 10.1016/j.canlet.2015.03.022

M3 - Article

VL - 362

SP - 106

EP - 115

JO - Cancer Letters

JF - Cancer Letters

SN - 0304-3835

IS - 1

ER -