The role of PPAR-γ system in normal and tumoral corticotroph pituitary and adrenal cells.

PPAR-gamma is a member of the nuclear hormone receptor superfamily of transcription factors, whose thiazolidinedione ligands (TZD) have been recently demonstrated to also possess anticancer properties in addition to their well-known insulin-sensitizer and glucose/lipid regulation activity. In this minireview, we summarize the current knowledge on PPAR-gamma in normal and tumoral corticotropic pituitary and adrenal cells. The receptor expression has been shown in ACTH-secreting cells in both normal and adenomal pituitary as well as in normal and tumor adrenal cortex. Preclinical studies conducted both in vitro on tumor cells and in vivo on xenograft tumor models obtained by subcutaneous injection of cancer cells have evidenced the anticancer properties of TZD, in particular rosiglitazone (RGZ) and pioglitazone (PIO). In both pituitary and adrenocortical cancer, RGZ treatment results in inhibition of cell proliferation, through G0/G1 cell-cycle arrest and induction of cell apoptosis, leading to significant inhibition of tumor growth in the xenograft tumor models. In addition, since RGZ can reduce ACTH and corticosterone secretion in mouse corticotropic pituitary tumors, both RGZ and PIO have been used in the treatment of Cushing's disease with variable but generally unsatisfactory results. Discrepancies in the antitumor effects of TZD observed between successful preclinical and unsuccessful clinical studies may be particularly due to differences in treatment duration and doses used