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Depletion of substrates for protein prenylation increases apoptosis in human periovulatory granulosa cells

Journal article
Authors Emilia Rung
P. Anders Friberg
Christina Bergh
Håkan Billig
Published in Molecular reproduction and development
Volume 73
Issue 10
Pages 1277-83
ISSN 1040-452X (Print)
Publication year 2006
Published at Institute of Neuroscience and Physiology, Department of Physiology
Institute of Clinical Sciences
Pages 1277-83
Language en
Links dx.doi.org/10.1002/mrd.20551
Keywords *Apoptosis/drug effects, Cells, Cultured, Cholesterol/*biosynthesis, Diterpenes/pharmacology, Estrenes/pharmacology, Farnesol/pharmacology, Farnesyltranstransferase/antagonists & inhibitors, Female, Furans/pharmacology, Granulosa Cells/drug effects/metabolism/*physiology, Hormone Antagonists/pharmacology, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology, Imidazoles/pharmacology, Leucine/analogs & derivatives/pharmacology, Mifepristone/pharmacology, Ovulation, Protein Isoprenylation/*drug effects, Quinolones/pharmacology, Receptors, Progesterone/antagonists & inhibitors
Subject categories Medical and Health Sciences, Physiology

Abstract

Progesterone receptor (PR) stimulation promotes survival in human and rat periovulatory granulosa cells. PR antagonists, Org 31710 and RU 486, both increase apoptosis and decrease cholesterol synthesis in these cells. The decrease in cholesterol synthesis also causes decreased synthesis of other products branching from the cholesterol synthesis pathway, including substrates for protein prenylation. In this study we focus on the link between apoptosis and prenylation in human periovulatory granulosa cells. A decreased cholesterol synthesis and increased apoptosis was verified in experiments with human periovulatory granulosa cells treated with the PR antagonists Org 31710 or RU 486 by measuring caspase-3/7 activity and incorporation of 14C-acetate into cholesterol and progesterone. Correspondingly, specific inhibition of cholesterol synthesis in periovulatory human granulosa cells using HMG-CoA reductase inhibitors (lovastatin or simvastatin) increased apoptosis, measured as caspase-3/7 activity. The increase in apoptosis caused by simvastatin or Org 31710 was partially reversed by addition of the protein prenylation precursors farnesol or geranylgeraniol. In addition, the prenylation inhibitors FTI R115777 and GGTI 2147 increased apoptosis in these cells. In conclusion our data suggest that PR antagonists increase apoptosis and reduce cholesterol synthesis in periovulatory granulosa cells and that the resulting depletion of substrates for protein prenylation may contribute to the increased apoptosis sensitivity.

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