PPARgamma inhibits GH synthesis and secretion and increases apoptosis of pituitary GH-secreting adenomas

Abstract

Objective: The objective of the study was to evaluate the expression and functional activity of Peroxisome proliferator-activated receptor (PPAR) g in pituitary adenomas from 14 consecutive acromegalic patients and to establish its role in apoptosis. Subjects and methods: Fourteen consecutive acromegalic patients were enrolled in the study. Wistar-Furth rats were used for in vivo studies. Expression of PPARg was evaluated by RT-PCR and Western blot. Apoptosis and cell cycle were assessed by FACS analysis. The effects of PPARg ligands on transcriptional regulation of GH gene were evaluated by RT-PCR and electromobility shift assay. Results: PPARg was expressed in all human GH-secreting adenoma (GH-oma), in normal pituitary tissue samples (39^24% and 78^5% of immunostained nuclei respectively; P , 0.0002; ANOVA), and in rat GH-secreting (GH3) cells. A PPRE-containing reporter plasmid transfected into GH3 cells was activated by ciglitazone or rosiglitazone (TZDs), indicating that PPARg was functionally active. Treatment of GH3 cells with TZDs increased apoptosis in a dose-dependent manner (P ¼ 0.0003) and arrested cell proliferation, reducing the number of cells in the S-phase (P , 0.0001 vs untreated cells). TZDs increased the expression of TRAIL, leaving unaffected that of p53 and Bax. TZDs reduced GH concentrations in the culture media from 43.7^5.4 ng/ml to 2.1^0.3 ng/ml (P , 0.0001) and in cell extracts (P , 0.004). PPARg-RXRa heterodimers bound to GH promoter, inhibiting its activity and reducing GH mRNA levels (1.8 £ 10 6 vs 5.7 £ 10 6 transcripts respectively vs untreated cells; P , 0.002). Subcutaneous GH-oma developed in rats injected with GH3 cells; tumor growth increased in placebo-treated rats and to a lesser extent in TZDs-treated animals (24.1^2.0 g, and 14.8^4.2 g respectively, P , 0.03). Serum GH concentrations were lower in TZDs-treated rats than in controls (871^67 ng/ml vs 1.309^238 ng/ml; P , 0.05). Conclusions:The results of this study indicate that PPARg controls GH transcription and secretion as well as apoptosis and growth of GH-oma; thus, TZDs have the potential of a useful tool in the complex therapeutic management of acromegalic patients.

Peroxisome Proliferator-Activated Receptor γ Is a Zac Target Gene Mediating Zac Antiproliferation

“…Consistent with our results, showing that Zac antiproliferation is mediated by PPARg, both proteins play a role in tumor suppression of breast cancer (4,(42)(43)(44) and pituitary adenomas (40,41,45,46). Acromegalic patients suffering from growth hormone (GH)-producing pituitary tumors are routinely treated with somatostatin analogues, such as octreotide.…”

“…To investigate if this concept also applies to endogenous Zac expression, we treated the rat pituitary tumor cell line GH3 (40,41) with the somatostatin analogue octreotide, which potently induces Zac expression through activated GSK3h-dependent pathways (10). We detected progressively increasing Zac mRNA levels following 6, 12, and 24 hours of treatment, which was accompanied by simultaneous elevation of Zac protein levels (Fig.…”

“…Although improvement in the signs and symptoms of acromegaly due to normalization of GH secretion is achieved in most cases (64-74%), only f30% of patients show tumor shrinkage (47). Interestingly, it has been shown that PPARg ligands suppress not only GH secretion but also proliferation of pituitary tumor cells in vivo (41,45,46). We show here that octreotide induces PPARg via Zac and, moreover, observe a synergistic growth inhibition by simultaneous treatment of pituitary tumor cells with octreotide and PPARg ligands (rosiglitazone, 15-D-PGJ2).…”

Insulin Resistance, Apoptosis, and Colorectal Adenoma Risk

“…In addition to promoting glucose metabolism, insulin has also been shown to promote DNA synthesis, stimulate cell division, and inhibit apoptosis in vitro (66) and in vivo (4). Elevated insulin may inhibit apoptosis by interacting with IGF-I receptor, enhancing nuclear factor-nB activation (67) or decreasing peroxisome proliferator-activated receptor-g activation (68).…”

The Transcription Factor Paired-Related Homeobox 1 (Prrx1) Inhibits Adipogenesis by Activating Transforming Growth Factor-β (TGFβ) Signaling

“…phRL-TK was from Promega (Madison, WI). pSG5-PPAR␥, containing cDNA of human PPAR␥, has been described previously (21). pcDNA3 was from Invitrogen.…”