Apoptotic effects of a progesterone receptor antagonist on rat granulosa cells are not mediated via reduced protein isoprenylation

Mol Reprod Dev. 2007 Oct;74(10):1317-26. doi: 10.1002/mrd.20711.

Abstract

Progesterone is a survival factor in rat periovulatory granulosa cells. The mechanisms involved are unclear but progesterone receptor (PGR) antagonists have been shown to inhibit cholesterol synthesis and induce apoptosis. Furthermore, reports suggest that statins induce apoptosis by inhibition of protein isoprenylation. Statins inhibit the rate-limiting step of the cholesterol synthesis, thereby reducing availability of intermediates used for the post-translational isoprenylation process. It has been suggested that PGR antagonists in a similar manner induce apoptosis by decreasing cholesterol synthesis and thereby protein isoprenylation. In this study we hypothesized that the mechanism by which the nuclear PGR antagonist Org 31,710 induces apoptosis in rat periovulatory granulosa cells, is by decreasing cholesterol synthesis and thereby general cell protein isoprenylation. Incubation of isolated granulosa cells with Org 31,710 or simvastatin for 22 hr resulted in increased apoptosis and reduced cholesterol synthesis. However, simvastatin caused a substantial inhibition of cholesterol synthesis after 6 hr in culture without inducing apoptosis. In contrast, Org 31,710 had only a modest effect on cholesterol synthesis after 6 hr while it significantly induced apoptosis. Addition of isoprenylation substrates partially reversed apoptosis induced by simvastatin and to a lesser extent apoptosis induced by Org 31,710. In addition, and in contrast to Org 31,710, simvastatin caused a decrease in isoprenylation of a selected isoprenylation marker protein, the Ras-related protein RAB11. In conclusion, we demonstrate that the PGR antagonist inhibits cholesterol synthesis in granulosa cells but reduced protein isoprenylation is not the mediating mechanism of increased apoptosis as previously hypothesized.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Cells, Cultured
  • Cholesterol / metabolism
  • Estrenes / pharmacology*
  • Female
  • Furans / pharmacology*
  • Granulosa Cells / cytology
  • Granulosa Cells / drug effects*
  • Granulosa Cells / metabolism
  • Hormone Antagonists / pharmacology
  • Hypolipidemic Agents / pharmacology
  • Protein Prenylation / drug effects*
  • Protein Prenylation / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Progesterone / antagonists & inhibitors*
  • Simvastatin / pharmacology

Substances

  • Estrenes
  • Furans
  • Hormone Antagonists
  • Hypolipidemic Agents
  • Receptors, Progesterone
  • Org 31710
  • Cholesterol
  • Simvastatin