| Title | Role of Isoprenylation in Simvastatin-Induced Inhibition of Ovarian Theca-Interstitial Growth in the Rat. | | Author(s) | Rzepczynska IJ, Piotrowski PC, Wong DH, Cress AB, Villanueva J, Duleba AJ | | Source | Biol Reprod 2009 Jul 1. | | Abstract | Statins are competitive inhibitors of 3-hydroxy-3methylglutaryl-Coenzyme A reductase (HMGCR), a rate limiting step of the mevalonate pathway. Pleiotropic effects of statins may be due to inhibition of cholesterol synthesis as well as decreased availability of several biologically important intermediate components of the mevalonate pathway including substrates for isoprenylation: farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Recently, we have demonstrated a statin-induced inhibition of ovarian theca-interstitial cell proliferation in vitro, as well as a reduction of testosterone levels in women with polycystic ovary syndrome (PCOS). This report evaluates the relative contribution of inhibition of isoprenylation and/or cholesterol availability to the modulation of theca-interstitial proliferation. Rat theca-interstitial cells were cultured in chemically defined media without or with simvastatin, FPP, GGPP, inhibitors of isoprenylation, squalene, and/or membrane-permeable forms of cholesterol: 25-hydroxycholesterol and 22-hydroxycholesterol. Simvastatin inhibited DNA synthesis and the count of viable cells. Effects of simvastatin were partly abrogated by both FPP and GGPP, but not by squalene or cholesterol. Inhibition of farnesyl transferase and geranylgeranyl transferase reduced cell proliferation. The present findings indicate that simvastatin inhibits proliferation of theca-interstitial cells, at least in significant part, by reduction of isoprenylation. These observations provide likely mechanisms explaining clinically observed improvement of ovarian hyperandrogenism in women with PCOS. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19571257 |
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