Role of the PPAR-γ System in Normal and Tumoral Pituitary Corticotropic Cells and Adrenal Cells

Abstract

PPAR-γ 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-γ 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.

Treatment of Cushing's disease: a mechanistic update

“…ACTH-secreting adenomas (Heaney 2004, Mannelli et al 2010. PPARg ligands, thiazolidinediones, have been shown to increase insulin sensitivity and also inhibit the growth of many tumors, including breast, colon, and prostate cancer cells (Mannelli et al 2010).…”

“…PPARg ligands, thiazolidinediones, have been shown to increase insulin sensitivity and also inhibit the growth of many tumors, including breast, colon, and prostate cancer cells (Mannelli et al 2010). In addition, antiproliferation with G0/G1 cell cycle arrest, and apoptotic effects in murine cell model of corticotrope adenoma cells and inhibition of POMC transcription were demonstrated using PPARg ligands (Heaney et al 2002).…”

“…Despite initial results indicating that rosiglitazone could be an effective treatment for patients with CD (Ambrosi et al 1990), further reports confirmed that PPARg ligands have no efficacy (Kreutzer et al 2009), a sustained ACTH decrease is rare, and ACTH levels may rebound (Suri & Weiss 2005, Morcos et al 2007). Current information is insufficient to support the routine clinical use of rosiglitazone or pioglitazone in patients with CD (Biller et al 2008, Mannelli et al 2010. Moreover, side effects such as edema, hypertension, weight gain, somnolence, hirsutism, and bruisability are significant, and there have also been concerns related to possible increased cardiovascular disease risks (Nissen & Wolski 2010).…”

Isorhamnetin Inhibits Proliferation and Invasion and Induces Apoptosis through the Modulation of Peroxisome Proliferator-activated Receptor γ Activation Pathway in Gastric Cancer

“…These have been found in all the mammalian species that have been examined to date (9,10). PPAR-␥ is highly expressed in cancer cells, and treatment with PPAR-␥ ligands can induce cell differentiation and apoptosis (11)(12)(13). Existing endogenous ligands for PPAR-␥ include polyunsaturated fatty acids and the eicosanoids 15-deoxy-⌬12,14-prostaglandin J2 (15d-PGJ2), 13-hydroxyoctadecadienoic acid, and 15-hydroxyeicosatetraenoic acid (14,15).…”

Management Approaches to Congenital Adrenal Hyperplasia in Adolescents and Adults; Latest Therapeutic Developments

“…The nuclear transcription factor, peroxisome proliferator-activated receptor gamma (PPAR-) affects the expression of a wide variety of genes. PPAR-is found in both the corticotrophs of the anterior pituitary and the adrenal cortex (Mannelli et al, 2010). Short, interfering RNA's (siRNA's) can silence transcription of normal or mutant genes as reported by Inoue et al, 2006.…”