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

Objective: The objective of the study was to evaluate the expression and functional activity of Peroxisome proliferator-activated receptor (PPAR) gamma 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 PPARgamma was evaluated by RT-PCR and Western blot. Apoptosis and cell cycle were assessed by FRCS analysis. The effects of PPARgamma ligands on transcriptional regulation of GH gene were evaluated by RT-PCR and electromobility shift assay. Results: PPARgamma 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 PPARgamma was functionally active. Treatment of GH3 cells with TZDs increased apoptosis in a dose-dependent manner (P = 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 +/- 5.4ng/ml to 2.1 +/- 0.3 ng/ml (P < 0.0001) and in cell extracts (P < 0.004). PPARgamma-RXRalpha heterodimers bound to GH promoter, inhibiting its activity and reducing GH mRNA levels (1.8 x 10(6) vs 5.7 x 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 +/- 67ng/ml vs 1.309 +/- 238 ng/ml; P < 0.05). Conclusions: The results of this study indicate that PPARgamma 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.