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This version published online on May 10, 2005
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-1267
A more recent version of this article appeared on July 1, 2005
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Submitted on July 1, 2004
Accepted on April 22, 2005

Peroxisome proliferator activated receptor gamma (PPAR{gamma}) agonists suppress adrenocortical tumor cell proliferation and induce differentiation

Matthias J. Betz, Igor Shapiro, Martin Fassnacht, Stefanie Hahner, Martin Reincke, Felix Beuschlein*, and for the German and Austrian Adrenal Network

Division of Endocrinology and Diabetes, Department of Internal Medicine II, University Hospital Freiburg, Germany; Division of Endocrinology, Department of Internal Medicine, University Hospital Würzburg, Germany; Department of Internal Medicine, University Hospital Innenstadt, Ludwig-Maximilians-University, Munich, Germany

* To whom correspondence should be addressed. E-mail: beuschlein{at}medizin.ukl.uni-freiburg.de.

Context. Thiazolidinediones (TZDs) have been implemented into clinical practice for the treatment of type 2 diabetes mellitus as specific PPAR{gamma} ligands. Moreover, recent evidence has suggested that TZDs might have favorable effects in the treatment of a variety of tumors as differentiation inducing agents. Adrenocortical carcinoma (ACC) is a rare tumor entity with poor prognosis due to its highly malignant phenotype and lack of effective treatment options.

Objective. To investigate effects of TZDs on adrenocortical cancer cells.

Results. PPAR{gamma} mRNA expression was detectable in all adrenocortical tumors including ACCs at similar levels. Furthermore, incubation of the adrenocortical tumor cell line NCI h295 with the PPAR{gamma} agonist rosiglitazone led to a decrease in cell viability, a decrease of cellular proliferation and an increase in apoptosis as well as increase in steroidogenesis. On the molecular level, NCI h295 cells expressed higher levels of ACTH receptor (MC2-R) mRNA upon treatment, while cyclin E mRNA was reduced, thus reflecting a shift towards an expression pattern found in less aggressive adrenocortical tumors in vivo. Accordingly, luciferase experiments confirmed an increased promoter activity for the MC2-R after stimulation with rosiglitazone. Co-incubation with the specific PPAR{gamma} antagonist GW9662 demonstrated the inhibition of TZD induced increase in steroidogenesis while growth suppression upon TZD treatment was not affected by GW9662.

Conclusions. Thus, both PPAR{gamma} dependent as well as PPAR{gamma} independent effects of TZD treatment are likely to contribute to the observed phenotypical effects on NCI h295 cells. Taken together, these data indicate that TZDs might have the potential to become an additional treatment option as differentiation inducing agents in patients with ACC.
Key words: PPAR{gamma} • rosiglitazone • adrenal • adrenocortical cancer • ACTH receptor




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