Mevastatin inhibits proliferation of rat ovarian theca-interstitial cells by blocking the mitogen-activated protein kinase pathway.
OBJECTIVE
To evaluate mechanisms involved in mevastatin-induced inhibition of proliferation of ovarian theca-interstitial cells.


METHODS
In vitro study.


METHODS
Academic laboratory.


METHODS
Immature Sprague-Dawley female rats.


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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Kwintkiewicz
Jakub
J
Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Foyouzi
Nastaran
N
Piotrowski
Piotr
P
Rzepczynska
Izabela
I
Duleba
Antoni J
AJ
D000818:Animals; D001769:Blood; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D004789:Enzyme Activation; D005260:Female; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008798:Mevalonic Acid / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D011374:Progesterone / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000494:pharmacology; D013799:Theca Cells / Q000166:cytology* / Q000201:enzymology*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007328:Insulin; C012258:mevastatin; D013739:Testosterone; D011374:Progesterone; D008148:Lovastatin; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D008798:Mevalonic Acid