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Cardiovascular Research 2004 64(2):346-355; doi:10.1016/j.cardiores.2004.06.024
© 2004 by European Society of Cardiology
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Copyright © 2004, European Society of Cardiology

Synergistic upregulation of low-density lipoprotein receptor activity by tamoxifen and lovastatin

Yajaira Suáreza,1, Carlos Fernándeza,1, Diego Gómez-Coronadoa, Antonio J. Ferrueloa, Alberto Dávalosa, Javier Martínez-Botasa and Miguel A. Lasuncióna,b,*

aServicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Ctra. de Colmenar, km 9, E-28034 Madrid, Spain
bDepartamento de Bioquímica y Biología Molecular, Universidad de Alcalá, 28771 Alcalá de Henares, Spain

* Corresponding author. Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Ctra. de Colmenar, km 9, E-28034, Madrid, Spain. Tel.: +34 91 3368077; fax: +34 91 3369016. Email address: miguel.a.lasuncion{at}hrc.es

Objective: To study the mechanism involved in the cholesterol-lowering activity of tamoxifen, an estrogen receptor (ER) modulator widely used in breast cancer therapy.

Methods and results: We used MOLT-4 cells, which do not express estrogen receptors and require important amounts of cholesterol for proliferation. We firstly confirmed that tamoxifen reduced cholesterol biosynthesis by inhibiting sterol {Delta}8,7-isomerase and {Delta}24-reductase activities, which resulted in the accumulation of zymosterol. In cells incubated in the presence of low-density lipoprotein (LDL) (120 µg cholesterol/ml), tamoxifen stimulated LDL receptor activity and expression in a dose-dependent manner, as determined by 1,1'-dioctadecyl-3,3,3,3'-tetramethylindocarbocyanineperchlorate (DiI)-labeled LDL uptake, LDL receptor expression on the cell surface and LDL receptor mRNA levels. Furthermore, tamoxifen, but not lovastatin, inhibited the egress of LDL-derived cholesterol from lysosomes, as ascertained by filipin staining in both MOLT-4 and HepG2 cells. When studied in combination, especially at relatively high LDL concentrations in the medium, tamoxifen and lovastatin stimulated LDL receptor activity synergistically, which is attributed to the different mechanism of action these drugs exhibit.

Conclusions: The present study demonstrates the stimulation of the LDL receptor by tamoxifen. These results explain the long-known hypolipidemic effect of tamoxifen and support its use, or that of other intracellular cholesterol trafficking inhibitors, in combination with statins for the reduction of plasma LDL cholesterol levels.

KEYWORDS Receptors; Cholesterol; Lipid metabolism; Lipoproteins; Statins

1 Y.S. and C.F. equally contributed to this study and should be considered as first author indistinctly.

Time for primary review 19 days


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