title: Simvastatin decreases invasiveness of human endometrial stromal cells.
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.
authors.affiliation: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of California Davis, Sacramento, California 95817, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Sokalska
authors.forename: Amanda
authors.initials: A
authors.lastname: Cress
authors.forename: Kaylon L
authors.initials: KL
authors.lastname: Bruner-Tran
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Osteen
authors.forename: Hugh S
authors.initials: HS
authors.lastname: Taylor
authors.forename: Israel
authors.initials: I
authors.lastname: Ortega
authors.forename: Antoni J
authors.initials: AJ
authors.lastname: Duleba
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D004715:Endometriosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004717:Endometrium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D011106:Polyisoprenyl Phosphates / Q000378:metabolism / Q000494:pharmacology; D054876:Prenylation / Q000187:drug effects; D012717:Sesquiterpenes / Q000378:metabolism / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology*; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; C560823:TIMP2 protein, human; D019716:Tissue Inhibitor of Metalloproteinase-2; C004808:farnesyl pyrophosphate; D019821:Simvastatin; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C002963:geranylgeranyl pyrophosphate