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

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.

Statins Inhibit Monocyte Chemotactic Protein 1 Expression in Endometriosis

“…22 The proposed mechanisms of actions of statins on endometriosis implants are stimulation of apoptosis, inhibition of endometrial cell proliferation, blockage of angiogenesis, disruption of adherence and invasion of endometrial cells to peritoneum, and decrease in oxidative stress and inflammation. 10,[22][23][24][25][26] Decreased sensitivity of endometrial tissue to spontaneous apoptosis contributes to the implantation and growth of endometrium at ectopic sites. 27 Ectopic endometriosis implants demonstrate high ERK1/2 signaling pathway activity resulting in enhanced cell survival.…”

“…28 Statins may decrease the proliferation of endometrial stromal cells by blocking the activation of this pathway. 24,25,28 Statins may also induce apoptotic cell death by stimulating caspase 3/7 in endometrial stromal cells. 26 In order to implant and grow, refluxed endometrial cells need to establish cell-to-cell or cell-to-extracellular matrix interactions with the peritoneal lining and invade extracellular matrix after initial attachment.…”

Treatment of Endometriosis with Non-Hormonal Agents: Review

“…İn-vitro olarak ektopik endometriyal stromal hücrelerin çoğalmalarının baskılan-masının hangi mekanizma ile oluştuğu henüz bilinmemektedir. 21 Esfandiari ve ark., in vitro çalışmalarında, levostatinin doza bağımlı olarak endometriyal hücrelerin çoğalmasını ve anjiyogenezisi engellediğini bildirmişlerdir. 22 Çakmak ve ark., simvastatin ile tedavi edilen endometriyozisli sıçanlarda monosit kemotaktik protein-1'in kontrol grubuna göre daha az düzeyde olduğunu bildirmişlerdir.…”

Novel Medical Treatment Modalities of Endometriosis

“…Nuclear factor kB is activated by cytokines such as TNF-α and IL-1b. It binds to DNA to determine favoring cell proliferation and inhibiting apoptosis in various cell types including endometrial and endometriotic cells [31][32][33][34] .…”

“…Cell proliferation, motility, adhesion, and invasion abilities were signifi cantly reduced, and apoptosis was increased in vitro [32][33][34] . NF-kB suppression was useful in reducing endometriosis establishment and progression in animal models and diminishing endometriosis-associated symptoms in women.…”