Synergistic upregulation of low-density lipoprotein receptor activity by tamoxifen and lovastatin.
OBJECTIVE
To study the mechanism involved in the cholesterol-lowering activity of tamoxifen, an estrogen receptor (ER) modulator widely used in breast cancer therapy.


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 microg 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.
Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Ctra. de Colmenar, km 9, E-28034 Madrid, Spain.
Yajaira
Y
Suárez
Carlos
C
Fernández
Diego
D
Gómez-Coronado
Antonio J
AJ
Ferruelo
Alberto
A
Dávalos
Javier
J
Martínez-Botas
Miguel A
MA
Lasunción
D045744:Cell Line, Tumor; D002784:Cholesterol / Q000096:biosynthesis; D008078:Cholesterol, LDL / Q000378:metabolism; D004357:Drug Synergism; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*; D008247:Lysosomes / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D013268:Stimulation, Chemical; D013629:Tamoxifen / Q000494:pharmacology*
D008078:Cholesterol, LDL; D020847:Estrogen Receptor Modulators; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011973:Receptors, LDL; D013629:Tamoxifen; D002784:Cholesterol; D008148:Lovastatin