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Statins Inhibit Growth of Human Endometrial Stromal Cells Independently of Cholesterol Availability¹

Department of OB/GYN,³ Yale University School of Medicine, New Haven, Connecticut 06520 Polish Academy of Sciences Medical Research Center,⁴ Warsaw 02-106, Poland Department of GYN/OB,⁵ Poznan University of Medical Sciences, Poznan 61-701, Poland

ABSTRACT

Endometriosis is characterized by ectopic growth of endometrial tissues. Statins, inhibitors of 3-hydroxy-3methylglutaryl-coenzyme A reductase (HMGCR), have been shown to decrease proliferation of several mesenchymal tissues. Actions of statins may be related to decreased availability of cholesterol as well as intermediate metabolites of the mevalonate pathway downstream of HMGCR. This study was designed to evaluate effects of statins on growth of endometrial stromal cells and to investigate mechanisms of these effects. Human endometrial stromal cells were cultured in the absence and in the presence of serum and with or without mevastatin and simvastatin. DNA synthesis and viable cell numbers were determined. Effects of statins were also evaluated in the presence of mevalonate and squalene. Furthermore, effects on phosphorylation of mitogen-activated protein kinase 3/1 (MAPK3/1) (also known as extracellular signal-regulated kinase [ERK1/2]) were determined. Mevastatin and simvastatin induced a concentration-dependent inhibition of DNA synthesis and viable cell count in chemically defined media and in the presence of serum. Mevalonate, but not squalene, abrogated inhibitory effects of statins on cell proliferation. Statins inhibited MAPK3/1 phosphorylation. This is the first study demonstrating that statins inhibit growth of endometrial stromal cells. This effect is also demonstrable in the presence of a supply of cholesterol and may be related to decreased activation of MAPK3/1. The present observations may be relevant to potential therapeutic use of statins in conditions such as endometriosis.

endometrial stroma, female reproductive tract, kinases, proliferation, signal transduction, statins, uterus

¹ Supported by NIH grant R01 HD40207 to A.J.D.

² Correspondence: Antoni J. Duleba, Department of Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520. FAX: 203 7857134; antoni.duleba{at}yale.edu

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