Mevastatin inhibits proliferation of rat ovarian theca-interstitial cells by blocking the mitogen-activated protein kinase pathway

Abstract

Objective: To evaluate mechanisms involved in mevastatin-induced inhibition of proliferation of ovarian theca-interstitial cells.

Design: In vitro study.

Setting: Academic laboratory.

Animal(s): Immature Sprague-Dawley female rats.

Intervention(s): Ovarian theca-interstitial cells were cultured without and with mevastatin in the presence and absence of serum, mevalonic acid, and/or insulin.

Main outcome measure(s): Proliferation was assessed by determination of DNA synthesis by thymidine incorporation assay. Activation of extracellular signal-regulated kinase (Erk1/2) and of Akt/protein kinase B (PKB) was determined by ELISA.

Result(s): Mevastatin induced a concentration-dependent inhibition of theca-interstitial cell proliferation in the absence and in the presence of serum. Inhibitory effects of mevastatin were partly abrogated by mevalonic acid and by insulin. Mevastatin blocked basal and insulin-induced phosphorylation of ERK1/2. In contrast, mevastatin had no significant effect on either basal or insulin-induced phosphorylation of Akt/PKB.

Conclusion(s): Mevastatin inhibits proliferation of theca-interstitial cells by a mechanism that involves depletion of mevalonic acid and selective inhibition of basal and insulin-induced activity of Erk1/2 pathway, but not Akt/PKB pathway. These effects of mevastatin may be a result of decreased isoprenylation of small GTPases.