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

Thiazolidinediones (TZDs) as specific ligands for the PPARγ have been implemented into clinical practice for the treatment of type 2 diabetes mellitus. More recently, in vitro and pre-clinical in vivo findings have suggested that TZDs might also have favorable effects in the treatment of a variety of tumors as differentiation inducing agents. Adrenocortical carcinoma (ACC) is a rare tumor with poor prognosis due to a highly malignant phenotype and lack of effective treatment options. Since most effects of TZDs are dependent upon the presence of PPARγ in the target tissue, we studied a series of 32 adrenocortical tumors for the expression of PPARγ. Interestingly, PPARγ mRNA was detectable in all tumors including ACCs at similar levels, while ACTH receptor (MC2-R) mRNA as a marker of differentiation varied widely between the tumor entities. To further explore the functional significance of these findings, the adrenocortical tumor cell line NCI h295 was treated with the PPARγ agonists rosiglitazone and cell viability, proliferation, apoptosis and steroidogenesis was monitored. Incubation with rosiglitazone led to a decrease in cell viability as measured by the MTT assay in a time-and dose-dependent manner. This decrease was paralleled by a decrease of cellular proliferation (BrdU assay) and increase in apoptosis as measured by caspase 3/7 activity. In contrast, rosiglitazone did not affect cellular viability of murine adrenal Y1 cells that do not express PPARγ. On the molecular level, NCI h295 cells expressed higher levels of MC2-R mRNA upon treatment, while cyclin E mRNA was reduced, thus reflecting a shift towards a expression pattern found in less aggressive adrenocortical tumors in vivo. Taken together, these data indicate that TZDs have the potential to become an additional treatment option as differentiation inducing agents in patients with ACC.