Simvastatin Decreases Invasiveness of Human Endometrial Stromal Cells1

Anna Sokalska, Sokalska A, Amanda B. Cress, Amanda Cress, Cress A, Kaylon L. Bruner‐Tran, Kaylon L Bruner-Tran, Kevin G. Osteen, Osteen KG, Hugh S. Taylor, Israel Ortega, Ortega I, Antoni J. Dulęba, Duleba AJ, Antoni J Duleba
Biology of reproduction · 2012 · vol. 87(1) , pp. 2, 1–6 · doi:10.1095/biolreprod.111.098806 · PMID:22492974 · PMC3406552 · W2106020828
article OA: bronze CC0 ⤵ 16 in-corpus citations
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Simvastatin decreased human endometrial stromal cell invasiveness and reduced MMP2, MMP3, and CD44 mRNA while increasing TIMP2 mRNA, with effects partially mediated by geranylgeranylation inhibition.

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Abstract

Recently we reported that statins, the competitive inhibitors of the key enzyme regulating the mevalonate pathway, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), decrease proliferation of human endometrial stromal (HES) cells. Furthermore, we found that simvastatin treatment reduces the number and the size of endometrial implants in a nude mouse model of endometriosis. The present study was undertaken to investigate the effect of simvastatin on HES cell invasiveness and on expression of selected genes relevant to invasiveness: matrix metalloproteinase 2 (MMP2), MMP3, tissue inhibitor of matrix metalloproteinase 2 (TIMP2), and CD44. Because statin-induced inhibition of HMGCR reduces the production of substrates for isoprenylation-geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP)-the effects of GGPP and FPP were also evaluated. Simvastatin induced a concentration-dependent reduction of invasiveness of HES cells. This effect of simvastatin was abrogated by GGPP but not by FPP. Simvastatin also reduced the mRNA levels of MMP2, MMP3, and CD44, but increased TIMP2 mRNA; all these effects of simvastatin were partly or entirely reversed in the presence of GGPP. The present findings provide a novel mechanism of action of simvastatin on endometrial stroma that may explain reduction of endometriosis in animal models of this disease. Furthermore, the presently described effects of simvastatin are likely mediated, at least in part, by inhibition of geranylgeranylation.

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Condition tags

endometriosis

MeSH descriptors

Endometriosis Endometrium Hydroxymethylglutaryl-CoA Reductase Inhibitors Simvastatin Animals Cell Adhesion Cell Adhesion Endometriosis Endometriosis Endometriosis Endometriosis Endometrium Endometrium Endometrium Female Gene Expression Gene Expression Humans Hyaluronan Receptors Hyaluronan Receptors

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