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.
authors: Faculty of Health Sciences, University of Macau, Av. Universidade, Taipa, Macau SAR, China; Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, 725 N Wolfe St, Baltimore, MD 21205, USA. Electronic address: jsshim@umac.mo.
authors: Joong Sup
authors: JS
authors: Shim
authors: Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, 725 N Wolfe St, Baltimore, MD 21205, USA.
authors: Ruo-Jing
authors: RJ
authors: Li
authors: Faculty of Health Sciences, University of Macau, Av. Universidade, Taipa, Macau SAR, China.
authors: Junfang
authors: J
authors: Lv
authors: Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, 725 N Wolfe St, Baltimore, MD 21205, USA.
authors: Sarah A
authors: SA
authors: Head
authors: Faculty of Health Sciences, University of Macau, Av. Universidade, Taipa, Macau SAR, China.
authors: Eun Ju
authors: EJ
authors: Yang
authors: Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, 725 N Wolfe St, Baltimore, MD 21205, USA. Electronic address: joliu@jhu.edu.
authors: Jun O
authors: JO
authors: Liu
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011960:Receptors, Estrogen / Q000378:metabolism*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D002784:Cholesterol
keywords: Angiogenesis; Cholesterol trafficking; Selective estrogen receptor modulator; Tamoxifen