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Inhibition of angiogenesis by selective estrogen receptor modulators through blockade of cholesterol trafficking rather than estrogen receptor antagonism
Shim J.S.1; Li R.-J.2; Lv J.1; Head S.A.2; Yang E.J.1; Liu J.O.2
2015
Source PublicationCancer Letters
ISSN18727980 03043835
Volume362Issue:1Pages:106-115
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.

KeywordAngiogenesis Cholesterol Trafficking Selective Estrogen Receptor Modulator Tamoxifen
DOI10.1016/j.canlet.2015.03.022
URLView the original
Indexed BySCI
Language英语
WOS Research AreaOncology
WOS SubjectOncology
WOS IDWOS:000353747700011
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Cited Times [WOS]:9   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Affiliation1.Universidade de Macau
2.The Johns Hopkins School of Medicine
Recommended Citation
GB/T 7714
Shim J.S.,Li R.-J.,Lv J.,et al. Inhibition of angiogenesis by selective estrogen receptor modulators through blockade of cholesterol trafficking rather than estrogen receptor antagonism[J]. Cancer Letters,2015,362(1):106-115.
APA Shim J.S.,Li R.-J.,Lv J.,Head S.A.,Yang E.J.,&Liu J.O..(2015).Inhibition of angiogenesis by selective estrogen receptor modulators through blockade of cholesterol trafficking rather than estrogen receptor antagonism.Cancer Letters,362(1),106-115.
MLA Shim J.S.,et al."Inhibition of angiogenesis by selective estrogen receptor modulators through blockade of cholesterol trafficking rather than estrogen receptor antagonism".Cancer Letters 362.1(2015):106-115.
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