PCB153 reduces apoptosis in primary cultures of murine pituitary cells through the activation of NF-κB mediated by PI3K/Akt.

Polychlorinated biphenyls (PCBs) are persistent pollutants involved in human tumorigenesis. PCB153 is a ubiquitous non-dioxin-like PCB with proliferative and anti-apoptotic effects. To explore the impact of PCB153 in the survival of pituitary cells, we exposed murine pituitary primary cells to PCB153 10 µM for 24 h. Apoptosis was assessed by RT-qPCR, Western-blot, immunoprecipitation, caspase activity, and immunofluorescence. We found that PCB153 decreased pituitary apoptosis through both the extrinsic and intrinsic pathways. PCB153 reduced the level of the pro-apoptotic protein p38-MAPK. Otherwise, PCB153 activated PI3K/Akt and Erk1/2 pathways and enhanced the expression and nuclear translocation of NF-κB. Cotreatments with specific inhibitors revealed that only PI3K/Akt changed the caspase-3 expression and NF-κB activation induced by PCB153. Also, PCB153 decreased the expression of the pro-apoptotic and pro-senescent cyclins p53 and p21. In summary, exposure to PCB153 leads to a downregulation of apoptosis in the pituitary driven by a PI3K/Akt-mediated activation of NF-κB.

Divergent Effects of Dioxin- or Non-Dioxin-Like Polychlorinated Biphenyls on the Apoptosis of Primary Cell Culture from the Mouse Pituitary Gland.

Polychlorinated biphenyls (PCBs) can disrupt the endocrine function, promote neoplasms and regulate apoptosis in some tissues; however, it is unknown whether PCBs can affect the apoptosis of pituitary cells. The study evaluated the effect of PCBs on the apoptosis of normal pituitary cells and the underlying mechanisms. Primary cell cultures obtained from mouse pituitary glands were exposed to Aroclor 1254 or selected dioxin-like (PCB 77, PCB 126) or non-dioxin-like (PCB 153, PCB 180) congeners. Apoptosis was evaluated by Annexin V staining, DNA fragmentation, and TUNEL assay. Both the expression and activity of caspases were analyzed. Selective thyroid hormone receptor (TR) or aryl-hydrocarbon receptor (AhR) or CYP1A1 antagonist were used to explore the mechanisms underlying PCBs action. Our results showed that Aroclor 1254 induced the apoptosis of pituitary cells as well as the final caspase-3 level and activity through the extrinsic pathway, as shown by the increased caspase-8 level and activity. On the other hand, the intrinsic pathway evaluated by measuring caspase-9 expression was silent. The selected non-dioxin-like congeners either increased (PCB 180) or reduced (PCB 153) pituitary cell apoptosis, affecting the extrinsic pathway (PCB 180), or both the extrinsic and intrinsic pathways (PCB 153), respectively. In contrast, the dioxin-like congeners (PCB 77 and PCB 126) did not affect apoptosis. The anti-apoptotic phenotype of PCB 153 was counteracted by a TR or a CYP1A1 antagonist, whereas the pro-apoptotic effect of PCB 180 was counteracted by an AhR antagonist. The induced apoptosis of Aroclor 1254 or PCB 180 was associated with a reduction of cell proliferation, whereas the decreased apoptosis due to PCB 153 increased cell proliferation by 30%. In conclusion, our data suggest that non-dioxin-like PCBs may modulate apoptosis and the proliferation rate of pituitary cells that have either pro- or anti-apoptotic effects depending on the specific congeners. However, the impact of PCBs on the process of pituitary tumorigenesis remains to be elucidated.

Growth hormone is necessary for the p53-mediated, obesity-induced insulin resistance in male C57BL/6J x CBA mice.

Insulin resistance is a key marker of both obesity and GH excess. The purpose of the study was to assess the role of GH on p53-mediated insulin resistance of male mice with obesity due to a high-fat diet. C57BL/6J × CBA male mice fed on a high-fat diet (Obe) were studied; male mice fed a normal diet (Lean) or transgenic mice for bovine GH under the same genetic background (Acro) served as controls. The convergence of p53 and GH pathways was evaluated by Western blot. Obe mice had insulin resistance, which was sustained by a selective increased expression of p53 in adipose tissue. Normal insulin sensitivity was restored, and adipose p53 expression normalized when the GH pathway was blocked. Only the adipose p53 expression was sensitive to the GH blockage, which occurred through the p38 pathway. Adipose tissue of Obe mice had a coordinate overexpression of suppressors of cytokine signal 1-3 and signal transducers and activators of transcription-1, -3, and -5b, not different from that of Acro mice, suggesting an increased sensitivity of adipose tissue to GH. On the contrary, Lean mice were unaffected by changes of GH action. GH seems to be necessary for the increased adipose p53 expression and for insulin resistance of obese mice.

Cardiac extrinsic apoptotic pathway is silent in young but activated in elder mice overexpressing bovine GH: interplay with the intrinsic pathway.

Apoptosis may occur through the mitochondrial (intrinsic) pathway and activation of death receptors (extrinsic pathway). Young acromegalic mice have reduced cardiac apoptosis whereas elder animals have increased cardiac apoptosis. Multiple intrinsic apoptotic pathways have been shown to be modulated by GH and other stimuli in the heart of acromegalic mice. However, the role of the extrinsic apoptotic pathways in acromegalic hearts is currently unknown. In young (3-month-old) acromegalic mice, expression of proteins of the extrinsic apoptotic pathway did not differ from that of wild-type animals, suggesting that this mechanism did not participate in the lower cardiac apoptosis levels observed at this age. On the contrary, the extrinsic pathway was active in elder (9-month-old) animals (as shown by increased expression of TRAIL, FADD, TRADD and increased activation of death inducing signaling complex) leading to increased levels of active caspase 8. It is worth noting that changes of some pro-apoptotic proteins were induced by GH, which seemed to have, in this context, pro-apoptotic effects. The extrinsic pathway influenced the intrinsic pathway by modulating t-Bid, the cellular levels of which were reduced in young and increased in elder animals. However, in young animals this effect was due to reduced levels of Bid regulated by the extrinsic pathway, whereas in elder animals the increased levels of t-Bid were due to the increased levels of active caspase 8. In conclusion, the extrinsic pathway participates in the cardiac pro-apoptotic phenotype of elder acromegalic animals either directly, enhancing caspase 8 levels or indirectly, increasing t-Bid levels and conveying death signals to the intrinsic pathway.

Regulation of cardiac fatty acids metabolism in transgenic mice overexpressing bovine GH.

Cardiac energy metabolism depends mainly on fatty acid (FA) oxidation; however, regulation of FA metabolism in acromegalic (Acro) heart is unknown. The aim of the study was to evaluate cardiac expression of key proteins of FA metabolism in young and elder transgenic mice overexpressing bovine GH Acro. Expression of proteins regulating FA entry into the cells, their uptake by mitochondria and beta-oxidation were evaluated by western blot, while FA content by Fourier transform infrared microspectrometry. Regulatory mechanisms of key steps of FA metabolism were also studied. The expression of plasma-membrane FA carriers (fatty acid-binding protein and fatty acid transport protein-1) and acylCoA synthetase was higher in young and lower in elder Acro than in corresponding controls; likewise, expression of cytoplasm to mitochondria-1 (CPT-1), the key enzyme of mitochondrial FA uptake, and that of medium-chain acyl-CoA dehydrogenase and long-chain acyl-CoA dehydrogenase, two regulatory beta-oxidation dehydrogenases, followed a similar pattern. FA content was lower in young and higher in elder Acro than in wild-type, suggesting an increased utilisation in young animals. GH regulated expression of key proteins of FA metabolism through changes in peroxisome proliferator-activated receptor alpha (PPARalpha) expression, which varied accordingly. GH effect was confirmed by treatment of Acro mice with a receptor antagonist, which abolished changes in key proteins of FA metabolism in young Acro. GH increased phosphorylation of AMP-activated protein kinase and anti-acetyl-CoA-carboxylase, two regulatory kinases, leading to lower CPT-1 inhibition by malonyl-CoA, and intervened in regulating PPARalpha expression through the ERK 1/2 pathway. In conclusion, chronic GH excess increased FA metabolism in the young age, whereas its action was overwhelmed in elder ages likely by GH-independent mechanisms, leading to reduced expression of key enzyme of FA metabolism.

Reduced colonic apoptosis in mice overexpressing bovine growth hormone occurs through changes in several kinase pathways.

OBJECTIVE: Growth hormone (GH) has antiapoptotic effects in several cell lines, including human colonic adenocarcinoma cells. In addition, it has been reported that patients with acromegaly have reduced apoptosis in colonic mucosa. The aim of the study was to investigate colonic apoptosis and underlying molecular mechanisms in transgenic mice overexpressing bovine GH (Acro) aged 3 months (young) or 9 months (elder). DESIGN AND METHODS: Apoptosis in colonic epithelial cells was evaluated by TUNEL and Annexin V; expression of pro- and anti-apoptotic proteins was assessed by Western blot. GH action was blocked treating Acro with a selective GH receptor antagonist. RESULTS: Young and elder Acro had lower colonic apoptosis [driven by GH through p38, p44/42 and PI3 kinase pathways], than littermate controls; changes were abolished by treating Acro with a selective GH receptor antagonist. The effects of GH were consistent with an anti-apoptotic phenotype (reduced cytosolic cytochrome-c, Bad and Bax and increased Bcl-2, and Bcl-XL level) leading to lower activation of caspase-9 and caspase-3. Changes in apoptotic proteins reversed after treatment with a GH receptor antagonist, suggesting a direct effect of GH. In addition, antiapoptotic phenotype of Acro had a protective role against doxorubicin-induced apoptosis. CONCLUSIONS: Our results suggest that GH leads to increased and reduced levels of anti- and pro-apoptotic proteins, respectively, lowering apoptosis in either young or elder transgenic animals through activation of several kinase pathways.

Changes in the expression of suppressor of cytokine signalling (SOCS) 2 in the colonic mucosa of acromegalic patients are associated with hyperplastic polyps.

BACKGROUND: Acromegalic patients have increased prevalence of colonic polyps. Development of hyperplastic polyps was related to suppressor of cytokine signalling (SOCS) 2 haploinsufficiency in animal models of acromegaly. OBJECTIVE AND PATIENTS: To evaluate whether variations in SOCS2 expression in the colonic mucosa of acromegalic patients might be associated to hyperplastic polyps, patients with active acromegaly or disease in remission with or without hyperplastic polyps were studied; controls were non-acromegalic subjects age- and sex- matched with or without polyps. MEASUREMENTS: Expression of SOCS1-3 was evaluated by RT-PCR, immunofluorescence and Western blot in the colonic mucosa. Coimmunoprecipatiton was used to evaluate multimeric protein complexes. RESULTS: Acromegalic patients with active disease and hyperplastic polyps had higher levels of SOCS2 transcripts; on the contrary, SOCS1 and SOCS3 transcripts did not differ among the study groups. While the expression of SOCS2 and SOCS3 protein was indistinguishable with that of the corresponding transcripts, SOCS1 protein expression was reduced in active acromegalic patients with polyps. SOCS1 protein was reduced owing to its increased proteasome degradation mediated by SOCS2. The increased SOCS2 and reduced SOCS1 led to increased STAT5b expression, suggesting a higher GH signalling transduction. CONCLUSIONS: Acromegalic patients with active disease and hyperplastic polyps have high levels of SOCS2 and increased SOCS1 degradation, leading to reduced negative feedback on GH signalling, likely favouring a hyperplastic polyps phenotype.

Serum pituitary antibodies in normal pregnancy and in patients with postpartum thyroiditis: a nested case-control study.

OBJECTIVES: The aim of this study was to evaluate antipituitary antibody (APA) prevalence in a series of patients with postpartum thyroiditis (PPT) during pregnancy and in the postpartum. DESIGN: We conducted a nested case-control study on consecutive PPT and normal pregnant women at the Centre for Endocrine and Diabetes Sciences in Cardiff and at the Department of Endocrinology in Pisa. METHODS: We enrolled 30 women with PPT: 17 were hypothyroid (Hypo), 7 with hyperthyroidism (Hyper) and 6 with a transient hyperthyroidism followed by hypothyroidism (Biphasic). Twenty-one healthy pregnant women served as controls. APA (measured using indirect immunofluorescence), free thyroxine, free triiodothyronine, TSH, antithyroid autoantibodies, and thyroid ultrasound were performed during pregnancy and postpartum. The stored sera have been sent to Pisa, where serum APA, IGF1, and cortisol were measured. RESULTS: APA were found in 8 out of the 30 PPT patients (26.7%) and in one normal pregnancy (4.7%, P=0.063). Three out of the seventeen Hypo with PPT (17.6%), three out of the seven Hyper PPT (42.8%), and two out of the six Biphasic PPT (33.3%) were positive for APA. APA prevalence was not significantly different in the PPT subgroups (P=0.453). With one exception, APA all increased in the postpartum period (87.5%, P<0.016). Basal serum IGF1 and cortisol were in the normal range with the exception of two patients with positive APA who presented low serum IGF1 levels (36 and 45 ng/ml). CONCLUSIONS: APA are frequently present in the postpartum period in patients affected by PPT. Further studies are necessary to evaluate whether APA in PPT patients are associated with pituitary function impairment.

Transgenic mice overexpressing growth hormone (GH) have reduced or increased cardiac apoptosis through activation of multiple GH-dependent or -independent cell death pathways.

GH has antiapoptotic effects in cardiac or noncardiac cell lines; however, increased apoptosis has been found in myocardial samples of patients with acromegaly. The aim of this study was to investigate cardiac apoptosis and underlying molecular mechanisms in transgenic mice overexpressing bovine GH [acromegalic mice (Acro)] aged 3 or 9 months. Cardiomyocyte apoptosis was evaluated by terminal deoxynucleotidyl transferase assay and annexin V; expression of pro- or antiapoptotic proteins was assessed by Western blot. Specificity of GH action was confirmed using a selective GH receptor antagonist. Apoptosis was lower in 3-month-old Acro than in controls; reduction was abolished by a GH receptor antagonist. The effects of GH were consistent with an antiapoptotic phenotype (increased Bcl2 and Bcl-XL and reduced Bad and cytochrome c levels, leading to lower activation of caspase-9 and caspase-3). In contrast, apoptosis was higher in 9-month-old Acro than in littermate controls; in addition, a GH receptor antagonist was without effect; the proapoptotic phenotype consisted in increased Bad, cytochrome c, caspase-9, and caspase-3. GH reduced apoptosis through p38 and p44/42 kinase pathways at young ages, whereas phosphatidylinositol-3-kinase was silent; on the contrary, the effects of GH on p38 and p44/42 kinase pathways were overcome by GH-independent stimuli in 9-month-old Acro. In addition, the antiapoptotic effect of GH was still present at this age as shown by phosphatidylinositol-3-kinase/Akt pathway activation. In conclusion, chronic GH excess reduced apoptosis at a young age, whereas its antiapoptotic action was overwhelmed in older animals by GH-independent mechanisms, leading to increased cell death.

Cardiac expression of adenine nucleotide translocase-1 in transgenic mice overexpressing bovine GH.

Heart hypertrophy is a common finding of acromegaly, a syndrome due to GH excess. Impairment of adenine nucleotide translocase-1 (ANT-1) gene, the main mitochondrial ADP/ATP exchanger, leads to cardiac hypertrophy. The aim of the study was to evaluate cardiac expression and the functional role of ANT-1 in 1- to 12-month-old transgenic mice overexpressing bovine GH (acromegalic mice, Acro) and littermate controls (wild-type mice, Wt). GH specificity of protein degree variation was assessed treating Acro with pegvisomant, a GH receptor competitor. Tissue levels of ANT-1, NF-kappaB, ATP, and lactic acid were evaluated by western blot, bioluminescence, and Fourier transform infrared spectroscopy respectively. The degree of ANT-1 expression was higher in 1-month-old Acro than in Wt (47+/-5% OD vs 33+/-4% OD, P<0 01). On the contrary, ANT-1 expression was lower in 3- to 12-month-old Acro than in Wt (P<0 03). Changes in ANT-1 expression were associated with consistent changes of cellular ATP content, increasing at 1 month (P<0 05) and reducing thereafter in Acro when compared with Wt (P<0 04). Treatment with pegvisomant abolished ANT-1 and ATP changes observed in 1- and 3-month-old Acro, thus supporting a GH-dependent mechanism. Reduced ATP generation in hypertrophied hearts of older Acro was associated with increased lactic acid levels suggesting that part of energy was due to glycolysis. Variations in ANT-1 expression were linked to GH through changes in NF-kappaB, the levels of which changed accordingly. In conclusion, 1-month-old acromegalic mice had increased ANT-1 expression and higher degree of ATP production. Long-standing disease was associated with a consistent reduction of ANT-1 and ATP tissue levels, which became GH-independent in older animals. This study demonstrated a direct effect of GH on key proteins involved in energy metabolism of acromegalic hearts.

Abnormal expression of PPAR gamma isoforms in the subcutaneous adipose tissue of patients with Cushing's disease.

BACKGROUND: Obesity is a clinical feature of patients with Cushing's disease. Peroxisome proliferators-activated receptor (PPAR)gamma is the master regulator of adipogenesis; however, the expression of PPARgamma isoforms in the subcutaneous adipose tissue (SAT) of patients with Cushing's disease is unknown. AIM AND METHODS: The expression of PPARgamma1 and PPARgamma2 was evaluated by real-time reverse transcription polymerase chain reaction (RT-PCR) and immunofluorescence (PPARgamma2 only) in SAT samples of 7 patients with untreated active Cushing's disease (Cushing(UNTR)), 8 with Cushing's disease in remission (Cushing(REM)) after pituitary adenomectomy, 15 normal lean subjects (Control(LEAN)), and 15 obese patients (Control(OBE)). RESULTS: Control(LEAN) had a higher degree of PPARgamma1 than PPARgamma2 (PPARgamma2/PPARgamma1 ratio, 0.55 +/- 0.35). PPARgamma2/PPARgamma1 ratio decreased in Cushing(UNTR) (0.10 +/- 0.043, P < 0.03 vs. Control(LEAN) and Control(OBE)), because of either increased PPARgamma1 or reduced PPARgamma2 expression. PPARgamma2/PPARgamma1 ratio was 0.48 +/- 0.07 in Cushing(REM) patients (P < 0.04 vs. Cushing(UNTR), P < 0.03 vs. Control(OBE)). PPARgamma2/PPARgamma1 ratio was higher in Control(OBE) 0.90 +/- 0.38 than in Control(LEAN) (P < 0.005 vs. Control(LEAN), P < 0.03 vs. Cushing(REM), P < 0.009 vs. Cushing(UNTR)). PPARgamma2/PPARgamma1 ratio was related to serum cortisol levels only in patients with Cushing'disease (r = 0.688, P < 0.02). CONCLUSIONS: Cushing(UNTR) patients had an abnormal expression of PPARgamma isoforms in SAT related to serum cortisol levels. Although further studies are necessary, it is conceivable that variations in the expression of PPARgamma isoforms might have a role in the abnormal adipogenesis of patients with Cushing's disease.

Apoptosis is reduced in the colonic mucosa of patients with acromegaly.

BACKGROUND: Patients with acromegaly have an increased risk of developing colonic tumours; reduced apoptosis is considered a leading mechanism in tumorigenesis. GH and IGF-1 decrease apoptosis in several cell lines including human colonic adenocarcinoma, but it is unknown whether epithelial cells of colonic mucosa of patients with acromegaly have reduced apoptosis. AIM: The aim of the study was to evaluate the degree of apoptosis in a cross-sectional study, in biopsy samples of colonic mucosa obtained from patients with acromegaly. PATIENTS AND METHODS: Eleven patients with active, untreated acromegaly (AcroUntr), 16 patients with acromegaly in remission (AcroRem) and 23 controls were enrolled in the study. Samples of colonic mucosa were obtained during colonoscopy; apoptosis was evaluated by either DNA fragmentation or terminal deoxynucleotidyl transferase assay. RESULTS: Apoptotic cells were 60.0 +/- 2.5% in samples of colonic mucosa of controls, 62.0 +/- 3.4% in those from patients with AcroRem (P = ns vs. controls), and 39.0 +/- 4.1% in those from patients with AcroUntr (P < 0.0001 vs. the other groups). Apoptosis was inversely related to serum IGF-I (r = 0.771, P < 0.001) or GH (r = 0.404, P = 0.05) levels and less to the estimated duration of disease (r = 0.384, P = 0.07). PPARgamma is considered to be a tumour suppressor gene the expression of which might be involved in colonic tumorigenesis. The expression of PPARgamma was lower in the colonic mucosa of patients with AcroUntr (2845 +/- 947 transcripts) than in that of controls (35 200 +/- 2450 transcripts) or AcroRem (29 547 +/- 3650 transcripts) (P < 0.005). The recovery of PPARgamma expression was associated with apoptosis in most cells. The lower degree of apoptosis in patients with AcroUntr was associated with a reduced expression of the antiapoptotic Bax protein. CONCLUSION: In conclusion, patients with AcroUntr have reduced apoptosis in colonic mucosa that is apparently reversed after acromegaly is cured. It is conceivable that reduced apoptosis may represent an early event in colonic tumorigenesis of patients with acromegaly.

PPARgamma 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 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.

Growth hormone inhibits apoptosis in human colonic cancer cell lines: antagonistic effects of peroxisome proliferator activated receptor-gamma ligands.

GH has antiapoptotic effects on several cells. However, the antiapoptotic mechanisms of GH on colonic mucosa cells are not completely understood. Peroxisome proliferator activated receptor-gamma (PPARgamma) activation enhances apoptosis, and a link between GH and PPARgamma in the colonic epithelium of acromegalic patients has been suggested. We investigated the effects of GH and of PPARgamma ligands on apoptosis in colonic cancer cell lines. Colonic cells showed specific binding sites for GH, and after exposure to 0.05-50 nm GH, their apoptosis reduced by 45%. The antiapoptotic effect was due to either GH directly or GH-dependent local production of IGF-1. A 55-85% reduction of PPARgamma expression was observed in GH-treated cells, compared with controls (P < 0.05). However, treatment of the cells with 1-50 microm ciglitazone (cig), induced apoptosis and reverted the antiapoptotic effects of GH by increasing the programmed cell death up to 3.5-fold at 30 min and up to 1.7-fold at 24 h. Expression of Bcl-2 and TNF-related apoptosis-induced ligand was not affected by either GH or cig treatment, whereas GH reduced the expression of Bax, which was increased by cig treatment. In addition, GH increased the expression of signal transducer and activator of transcription 5b, which might be involved in the down-regulation of PPARgamma expression. In conclusion, GH may exert a direct antiapoptotic effect on colonic cells, through an increased expression of signal transducer and activator of transcription 5b and a reduction of Bax and PPARgamma. The reduced GH-dependent apoptosis can be overcome by PPARgamma ligands, which might be useful chemopreventive agents in acromegalic patients, who have an increased colonic polyps prevalence.

Changes in the expression of the peroxisome proliferator-activated receptor gamma gene in the colonic polyps and colonic mucosa of acromegalic patients.

Acromegalic patients have an increased prevalence of colonic neoplasms and lower peroxisome proliferator-activated receptor gamma (PPARgamma) levels, the latter acting as a tumor suppressor gene. In this study we evaluated the expression of PPARgamma in the biopsy samples of the polyps and outside polyps colonic mucosa from seven patients with active, untreated acromegaly, 11 with cured disease, and 15 controls. Serum GH and IGF-I levels were higher in patients with untreated acromegaly than in those with acromegaly in remission or controls (P = 0.003 and P = 0.002, respectively) The expression of PPARgamma mRNA (mean +/- SE) was 1) mucosa outside polyps, 24,188 +/- 3,254 transcripts in the controls, 22,432 +/- 2,006 transcripts in acromegaly in remission, and 1,952 +/- 342 transcripts in untreated acromegaly (P < 0.0001 vs. controls and acromegaly in remission); and 2) polyps mucosa, 1,554 +/- 236 transcripts in the controls, 1,112 +/- 143 in acromegaly in remission, and 1,570 +/- 251 in untreated acromegaly (P = NS among polyps groups and mucosa outside polyps of untreated acromegaly; P < 0.0001 vs. mucosa outside polyps of controls and acromegaly in remission). Eighty-five percent of the cells in the mucosa outside polyps from controls or acromegaly in remission were positive at immunohistochemistry, at variance with 45% of the cells from polyps mucosa from each group and from those of mucosa outside polyps of untreated acromegaly (P = 0.0002). In conclusion, patients with untreated acromegaly have reduced expression of PPARgamma in the mucosa outside polyps, which might be reversed by curing the disease; conversely, patients with acromegaly in remission have the same low levels of expression of PPARgamma in the polyps mucosa as untreated acromegaly or controls, supporting the concept that reduced expression of PPARgamma might be an early event in colonic tumorigenesis.