Received for publication July 19, 2006.
Revised November 26, 2006.
Accepted for publication November 30, 2006.

PIOGLITAZONE INHIBITS ANDROGEN PRODUCTION IN NCI-H295R CELLS BY REGULATING GENE EXPRESSION OF CYP17 AND HSD3B2

Abstract

Thiazolidinediones (TZD) such as pioglitazone and rosiglitazone are widely used as insulin sensitizers in the treatment of type 2 diabetes. In diabetic women with polycystic ovary syndrome (PCOS), treatment with pioglitazone or rosiglitazone improves insulin resistance and hyperandrogenism, but the mechanism by which TZDs downregulate androgen production is unknown. Androgens are synthesized in the human gonads as well as the adrenals. We studied the regulation of androgen production by analysing the effect of pioglitazone and rosiglitazone on steroidogenesis in human adrenal NCI-H295R cells, an established in vitro model of steroidogenesis of the human adrenal cortex. Both TZDs changed the steroid profile of the NCI-H295R cells and inhibited the activities of P450c17 and 3HSDII, key enzymes of androgen biosynthesis. Pioglitazone but not rosiglitazone inhibited the expression of the CYP17 and HSD3B2 genes. Similarly, pioglitazone repressed basal and 8Br-cAMP-stimulated activities of CYP17 and HSD3B2 promoter reporters in NCI-H295R cells. However, pioglitazone did not change the activity of a cAMP responsive luciferase reporter indicating that it does not influence cAMP/PKA/CREBP signaling. Although PPAR is the nuclear receptor for TZDs, suppression of PPAR by siRNA technique did not alter the inhibitory effect of pioglitazone on CYP17 and HSD3B2 expression, suggesting that pioglitazone's action is independent of PPAR. On the other hand treatment of NCI-H295R cells with MEK/ERK inhibitor PD98059 enhanced promoter activity and expression of CYP17. This effect was reversed by pioglitazone treatment, indicating that the MEK/ERK signaling pathway plays a role in regulating androgen biosynthesis by pioglitazone.

Key words: Sex hormones, PPARs, MAP Kinase, Regulation - transcriptional, Endocrine cells

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