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) 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 FACS 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+/-5.4 ng/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+/-67 ng/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.

• Authors: Fausto Bogazzi, Federica Ultimieri, Francesco Raggi, Dania Russo, Renato Vanacore, Chiara Guida, Paolo Viacava, Denise Cecchetti, Giovanni Acerbi, Sandra Brogioni, Chiara Cosci, Maurizio Gasperi, Luigi Bartalena, Enio Martino
• Journal: European journal of endocrinology (Eur J Endocrinol) Vol. 150 Issue 6 Pg. 863-75 (Jun 2004) ISSN: 0804-4643 [Print] England
• PMID: 15191358 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Annexin A5
• Ligands
• Receptors, Cytoplasmic and Nuclear
• Thiazolidinediones
• Transcription Factors
• Rosiglitazone
• Human Growth Hormone
• ciglitazone

Topics

• Adenoma (metabolism, pathology)
• Animals
• Annexin A5 (metabolism)
• Apoptosis (physiology)
• Cell Line
• DNA Fragmentation
• Female
• Gene Expression (drug effects)
• Human Growth Hormone (biosynthesis, genetics, metabolism)
• Humans
• Ligands
• Mice
• Mice, Nude
• NIH 3T3 Cells
• Pituitary Neoplasms (metabolism, pathology)
• Promoter Regions, Genetic (genetics)
• Rats
• Rats, Inbred WF
• Receptors, Cytoplasmic and Nuclear (genetics, physiology)
• Reverse Transcriptase Polymerase Chain Reaction
• Rosiglitazone
• Thiazolidinediones (pharmacology)
• Transcription Factors (genetics, physiology)
• Transcription, Genetic (drug effects)
• Transfection