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The Mechanism for Protein Kinase C Inhibition of Androgen Production and 17-Hydroxylase Expression in a Theca Cell Tumor Model

Department of Obstetrics and Gynecology (V.E.B., J.C.H., B.R.C.), University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235-9032; Department of Pharmaco-Biology (R.S.), University of Calabria, 87036 Arcavacata di Rende (CS), Italy; Department of Physiology (P.Y., W.E.R.), Medical College of Georgia, Augusta, Georgia 30912; and Department of Pathology (T.S.), Tohoku University School of Medicine, Sendai 980-8575, Japan

Address all correspondence and requests for reprints to: Bruce R. Carr, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75235-9032. E-mail: Bruce.Carr{at}UTSouthwestern.edu.

Introduction: In polycystic ovary syndrome (PCOS), there is increased formation of androgens by thecal cells. Moreover, PCOS ovaries have been shown to have decreased levels of c-fos transcription factor. We hypothesize that c-fos expression inhibits 17-hydroxylase 17,20 lyase (CYP17) activity in the human ovary, and its decreased expression seen in PCOS may lead to elevated CYP17 transcription, resulting in increased androgen production.

Objective: Our objective was to define the role of the activator protein-1 transcription factors, namely c-fos, in the regulation of CYP17 expression in theca cells.

Methods: Human ovarian thecal-like tumor cells were used for all experiments. The following techniques were used: steroid quantification, mRNA extraction, microarray analysis, transfection, small interfering RNA, and immunohistochemistry.

Results: Stimulation of human ovarian thecal-like tumor cells with the protein kinase A pathway activator forskolin resulted in stimulation of C19 androgen production. In contrast, treatment with the protein kinase C pathway activator tetradecanoylphorbol acetate (TPA) resulted in decreased androgen production with a shift toward C21 progesterone production. TPA also led to complete inhibition of CYP17. Microarray data showed a 37-fold increase in c-fos after treatment with TPA. Transfection with steroidogenic factor 1 resulted in an increase in CYP17 promoter activity, which was significantly inhibited in the presence of c-fos. c-fos gene silencing led to an increase in CYP17 mRNA levels. Immunohistochemical staining for c-fos in ovaries demonstrated strong staining in granulosa cells, but not theca.

Conclusions: The activator protein-1 transcription factor c-fos plays a role in the inhibition of CYP17 expression. The decreased levels of c-fos expression in polycystic ovaries may be responsible for increased CYP17 levels in PCOS.