Peroxisome Proliferator-Activated Receptor-γ Agonists Suppress Adrenocortical Tumor Cell Proliferation and Induce Differentiation

Abstract

Thiazolidinediones (TZDs) have been implemented into clinical practice for the treatment of type 2 diabetes mellitus as specific peroxisome proliferator-activated receptor (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. The purpose of this study was to investigate effects of TZDs on adrenocortical cancer cells. PPARgamma 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 PPARgamma agonist rosiglitazone led to a decrease in cell viability, a decrease of cellular proliferation, and an increase in apoptosis as well as steroidogenesis. On the molecular level, NCI h295 cells expressed higher levels of ACTH receptor (melanocortin receptor-2) mRNA upon treatment, whereas cyclin E mRNA was reduced, thus reflecting a shift toward an expression pattern found in less aggressive adrenocortical tumors in vivo. Accordingly, luciferase experiments confirmed an increased promoter activity for the melanocortin receptor-2 after stimulation with rosiglitazone. Coincubation with the specific PPARgamma antagonist GW9662 demonstrated the inhibition of TZD-induced increase in steroidogenesis, whereas growth suppression upon TZD treatment was not affected by GW9662. Thus, both PPARgamma-dependent and PPARgamma-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.