Correction: Lycopene and Beta-Carotene Induce Growth Inhibition and Proapoptotic Effects on ACTH-Secreting Pituitary Adenoma Cells.
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ABSTRACT:
SUBMITTER: Haddad NF
PROVIDER: S-EPMC4743989 | biostudies-literature | 2016
REPOSITORIES: biostudies-literature
Publications
Correction: Lycopene and Beta-Carotene Induce Growth Inhibition and Proapoptotic Effects on ACTH-Secreting Pituitary Adenoma Cells.
Haddad Natália F NF Teodoro Anderson J AJ de Oliveira Felipe Leite FL Soares Nathália N de Mattos Rômulo Medina RM Hecht Fábio F Dezonne Rômulo Sperduto RS Vairo Leandro L dos Santos Goldenberg Regina Coeli RC Gomes Flávia Carvalho Alcântara FC de Carvalho Denise Pires DP Gadelha Mônica R MR Nasciutti Luiz Eurico LE Miranda-Alves Leandro L
PloS one 20160205 2
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Project description:An effective treatment for the management of adrenocorticotropic hormone-secreting pituitary adenomas (ACTH-PA) is currently lacking, although surgery is a treatment option. We have integrated information obtained at the metabolomic and proteomic levels to identify critical networks and signaling pathways that may play important roles in the metabolic regulation of ACTH-PA and therefore hopefully represent potential therapeutic targets. Six ACTH-PAs and seven normal pituitary glands were investigated via gas chromatography-mass spectrometry (GC-MS) analysis for metabolomics. Five ACTH-PAs and five normal pituitary glands were subjected to proteomics analysis via nano liquid chromatography tandem-mass spectrometry (nanoLC-MS/MS). The joint pathway analysis and network analysis was performed using MetaboAnalyst 3.0. software. There were significant differences of metabolites and protein expression levels between the ACTH-PAs and normal pituitary glands. A proteomic analysis identified 417 differentially expressed proteins that were significantly enriched in the Myc signaling pathway. The protein-metabolite joint pathway analysis showed that differentially expressed proteins and metabolites were significantly enriched in glycolysis/gluconeogenesis, pyruvate metabolism, citrate cycle (TCA cycle), and the fatty acid metabolism pathway in ACTH-PA. The protein-metabolite molecular interaction network identified from the metabolomics and proteomics investigation resulted in four subnetworks. Ten nodes in subnetwork 1 were the most significantly enriched in cell amino acid metabolism and pyrimidine nucleotide metabolism. Additionally, the metabolite-gene-disease interaction network established nine subnetworks. Ninety-two nodes in subnetwork 1 were the most significantly enriched in carboxylic acid metabolism and organic acid metabolism. The present study clarified the pathway networks that function in ACTH-PA. Our results demonstrated the presence of downregulated glycolysis and fatty acid synthesis in this tumor type. We also revealed that the Myc signaling pathway significantly participated in the metabolic changes and tumorigenesis of ACTH-PA. This data may provide biomarkers for ACTH-PA diagnosis and monitoring, and could also lead to the development of novel strategies for treating pituitary adenomas.
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Project description:Adrenocorticotrophin (ACTH)-secreting pituitary adenoma, also known as Cushing disease (CD), is rare and causes metabolic syndrome, cardiovascular disease and osteoporosis due to hypercortisolism. However, the molecular pathogenesis of CD is still unclear because of a lack of human cell lines and animal models. Here, we study 106 clinical characteristics and gene expression changes from 118 patients, the largest cohort of CD in a single-center. RNA deep sequencing is used to examine genotypic changes in nine paired female ACTH-secreting pituitary adenomas and adjacent nontumorous pituitary tissues (ANPT). We develop a novel analysis linking disease clinical characteristics and whole transcriptomic changes, using Pearson Correlation Coefficient to discover a molecular network mechanism. We report that osteoporosis is distinguished from the phenotype and genotype analysis. A cluster of genes involved in osteoporosis is identified using Pearson correlation coefficient analysis. Most of the genes are reported in the bone related literature, confirming the feasibility of phenotype-genotype association analysis, which could be used in the analysis of almost all diseases. Secreted phosphoprotein 1 (SPP1), collagen type I α 1 chain (COL1A1), 5'-nucleotidase ecto (NT5E), HtrA serine peptidase 1 (HTRA1) and angiopoietin 1 (ANGPT1) and their signalling pathways are shown to be involved in osteoporosis in CD patients. Our discoveries provide a molecular link for osteoporosis in CD patients, and may open new potential avenues for osteoporosis intervention and treatment.
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Project description:ACTH-secreting pituitary tumors are by definition partially autonomous, i.e., secrete ACTH independent of physiological control. However, only few, small-sized studies on proopiomelanocortin (POMC) and its regulation by corticotropin-releasing hormone (CRH) or glucocorticoids are available. Objective of the present study was to report on constitutive and CRH- and dexamethasone-regulated POMC, CRH (CRH-R1), and glucocorticoid receptor (NR3C1) gene expression in a large series of human corticotrope adenomas. Fifty-three ACTH-secreting adenomas were incubated with 10 nM CRH or 10 nM dexamethasone for 24 h. POMC, CRH-R1, NR3C1, and its alpha and beta isoforms were quantified and medium ACTH measured. Constitutive POMC expression proved extremely variable, with macroadenomas exhibiting higher levels than microadenomas. POMC increased during CRH in most specimens; conversely, changes induced by dexamethasone were varied, ranging from decrease to paradoxical increase. No correlation between POMC and ACTH was detected in any experimental condition. CRH-R1 expression was not linked to the response to CRH while NR3C1 was expressed at greater levels in specimens who failed to inhibit during dexamethasone; glucocorticoid receptor α was the more abundant isoform and subject to down-regulation by dexamethasone. Our results demonstrate a considerable variability in POMC expression among tumors and no correlation between POMC and ACTH, suggesting that POMC peptide processing/transport plays a major role in modulating ACTH secretion. Further, CRH-R1 and NR3C1 expression were not linked to the expected ligand-induced outcome, indicating that receptor signaling rather than abundance determines corticotrope responses. Our findings pave the way to new avenues of research into Cushing's disease pathophysiology.
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Project description:BackgroundA 40-year-old woman presented with galactorrhea and oligomenorrhea. She had a history of multiple ovarian cysts and pelvic pain.InvestigationsLaboratory evaluation included measurements of the levels of estradiol, follicle-stimulating hormone, luteinizing hormone, prolactin, thyroid-stimulating hormone, free endogenous T4, the glycoprotein hormone alpha subunit, cortisol, adrenocorticotropic hormone, and insulin-like growth factor I. Radiological studies included MRI of the pituitary.DiagnosisOvarian hyperstimulation syndrome caused by a pituitary adenoma, secreting follicle-stimulating hormone.ManagementThe patient underwent trans-sphenoidal resection of the adenoma, with subsequent normalization of hormonal values and symptoms.
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Project description:Corticotropin (ACTH)-secreting pituitary adenomas give rise to a severe endocrinological disorder, i.e., Cushing’s disease, with multifaceted clinical presentation and treatment outcomes. Experimental studies suggested that disease variability is inherent to the pituitary tumor, thus pointing to the need for further studies into tumor biology. Aim of the present study was to evaluate transcriptome expression pattern in a large series of ACTH-secreting pituitary adenoma specimens, in order to identify molecular signatures of these tumors. Gene expression profiling of formalin-fixed paraffin-embedded specimens from 40 human ACTH-secreting pituitary adenomas revealed significant expression of genes involved in protein biosynthesis and ribosomal function, in keeping with neuroendocrine cell profile. Unsupervised cluster analysis identified three distinct gene profile clusters and several genes were uniquely overexpressed in a given cluster, accounting for different molecular signatures. Of note, gene expression profiles were associated with clinical features such as age and size of the tumor. Altogether, our study shows that corticotrope tumors are characterized by neuroendocrine gene expression profile and present subgroup-specific molecular features.
2018-06-18 | GSE93825 | GEO
Project description:(1) Background. Cushing's disease presents gender disparities in prevalence and clinical course. Little is known, however, about sexual dimorphism at the level of the corticotrope adenoma itself. The aim of the present study was to evaluate molecular features of ACTH-secreting pituitary adenomas collected from female and male patients with Cushing's disease. (2) Methods. We analyzed 153 ACTH-secreting adenomas collected from 31 men and 122 women. Adenomas were established in culture and ACTH synthesis and secretion assessed in basal conditions as well as during incubation with CRH or dexamethasone. Concurrently, microarray analysis was performed on formalin-fixed specimens and differences in the expression profiles between specimens from male and female patients identified. (3) Results. ACTH medium concentrations in adenomas obtained from male patients were significantly lower than those observed in adenomas from female patients. This could be observed for baseline as well as modulated secretion. Analysis of corticotrope transcriptomes revealed considerable similarities with few, selected differences in functional annotations. Differentially expressed genes comprised genes with known sexual dimorphism, genes involved in tumour development and genes relevant to pituitary pathophysiology. (4) Conclusions. Our study shows for the first time that human corticotrope adenomas present sexual dimorphism and underlines the need for a gender-dependent analysis of these tumours. Differentially expressed genes may represent the basis for gender-tailored target therapy.
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Project description:Pituitary organoids are promising graft sources for transplantation in treatment of hypopituitarism. Building on development of self-organizing culture to generate pituitary-hypothalamic organoids (PHOs) using human pluripotent stem cells (hPSCs), we established techniques to generate PHOs using feeder-free hPSCs and to purify pituitary cells. The PHOs were uniformly and reliably generated through preconditioning of undifferentiated hPSCs and modulation of Wnt and TGF-β signaling after differentiation. Cell sorting using EpCAM, a pituitary cell-surface marker, successfully purified pituitary cells, reducing off-target cell numbers. EpCAM-expressing purified pituitary cells reaggregated to form three-dimensional pituitary spheres (3D-pituitaries). These exhibited high adrenocorticotropic hormone (ACTH) secretory capacity and responded to both positive and negative regulators. When transplanted into hypopituitary mice, the 3D-pituitaries engrafted, improved ACTH levels, and responded to in vivo stimuli. This method of generating purified pituitary tissue opens new avenues of research for pituitary regenerative medicine.
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Project description:Prior study has demonstrated that gut microbiota at the genus level is significantly altered in patients with growth hormone (GH)-secreting pituitary adenoma (GHPA). Yet, no studies exist describing the state of gut microbiota at species level in GHPA. We performed a study using 16S rRNA amplicon sequencing in a cohort of patients with GH-secreting pituitary adenoma (GHPA, n = 28) and healthy controls (n = 67). Among them, 9 patients and 10 healthy controls were randomly chosen and enrolled in metagenomics shotgun sequencing, generating 280,426,512 reads after aligning to NCBI GenBank DataBase to acquire taxa information at the species level. Weighted UniFrac analysis revealed that microbial diversity was notably decreased in patients with GHPA, consistent with a previous study. With 16S rRNA sequencing, after correction for false-discovery rate (FDR), rank-sum test at the genus level revealed that the relative abundance of Oscillibacter and Enterobacter was remarkably increased in patients and Blautia and Romboutsia genera predominated in the controls, augmented by additional LEfSe (linear discriminant analysis effect size) analysis. As for further comparison at the species level with metagenomics sequencing, rank-sum test together with LEfSe analysis confirmed the enrichment of Alistipes shahii and Odoribacter splanchnicus in the patient group. Notably, LEfSe analysis with metagenomics also demonstrated that Enterobacter sp. DC1 and Enterobacter sp. 940 PEND, derived from Enterobacter, were both significantly enriched in patients. Functional analysis showed that amino acid metabolism pathway was remarkably enriched in GHPA, while carbohydrate metabolism pathway was notably enriched in controls. Further, significant positive correlations were observed between Enterobacter and baseline insulin-like growth factor 1 (IGF-1), indicating that Enterobacter may be strongly associated with GH/IGF-1 axis in GHPA. Our data extend our insight into the GHPA microbiome, which may shed further light on GHPA pathogenesis and facilitate the exploration of novel therapeutic targets based on microbiota manipulation. IMPORTANCE Dysbiosis of gut microbiota is associated not only with intestinal disorders but also with numerous extraintestinal diseases. Growth hormone-secreting pituitary adenoma (GHPA) is an insidious disease with persistent hypersecretion of GH and IGF-1, causing increased morbidity and mortality. Researches have reported that the GH/IGF-1 axis exerts its own influence on the intestinal microflora. Here, the results showed that compared with healthy controls, GHPA patients not only decreased the alpha diversity of the intestinal flora but also significantly changed their beta diversity. Further, metagenomics shotgun sequencing in the present study exhibited that Enterobacter sp. DC1 and Enterobacter sp. 940 PEND were enriched in patients. Also, we were pleasantly surprised to find that the Enterobacter genus was strongly positively correlated with baseline IGF-1 levels. Collectively, our work provides the first glimpse of the dysbiosis of the gut microbiota at species level, providing a better understanding of the pathophysiological process of GHPA.
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Project description:Cushing disease is a condition in which the pituitary gland releases excessive adrenocorticotropic hormone (ACTH) as a result of an adenoma arising from the ACTH-secreting cells in the anterior pituitary. ACTH-secreting pituitary adenomas lead to hypercortisolemia and cause significant morbidity and mortality. Pituitary-directed medications are mostly ineffective, and new treatment options are needed. As these tumors express EGFR, we tested whether EGFR might provide a therapeutic target for Cushing disease. Here, we show that in surgically resected human and canine corticotroph cultured tumors, blocking EGFR suppressed expression of proopiomelanocortin (POMC), the ACTH precursor. In mouse corticotroph EGFR transfectants, ACTH secretion was enhanced, and EGF increased Pomc promoter activity, an effect that was dependent on MAPK. Blocking EGFR activity with gefitinib, an EGFR tyrosine kinase inhibitor, attenuated Pomc expression, inhibited corticotroph tumor cell proliferation, and induced apoptosis. As predominantly nuclear EGFR expression was observed in canine and human corticotroph tumors, we preferentially targeted EGFR to mouse corticotroph cell nuclei, which resulted in higher Pomc expression and ACTH secretion, both of which were inhibited by gefitinib. In athymic nude mice, EGFR overexpression enhanced the growth of explanted ACTH-secreting tumors and further elevated serum corticosterone levels. Gefitinib treatment decreased both tumor size and corticosterone levels; it also reversed signs of hypercortisolemia, including elevated glucose levels and excess omental fat. These results indicate that inhibiting EGFR signaling may be a novel strategy for treating Cushing disease.
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Project description:ContextSubclinical pituitary hemorrhage, necrosis, and/or cystic degeneration (SPH) presents mainly in large tumors and prolactinomas. The characteristics of patients with Cushing disease (CD) and SPH are not known.ObjectiveTo determine if SPH affects the presentation and biochemical profile of young patients with CD.MethodsPediatric and adolescent patients who were diagnosed with CD between 2005 and 2021 and available magnetic resonance imaging images were evaluated for SPH. The clinical and biochemical characteristics of patients with and without SPH were compared.ResultsEvidence of possible SPH was present in 12 out of 170 imaging studies (7.1%). Patients with and without SPH had similar age at diagnosis and sex distribution but differed in disease duration (median duration: 1.0 year [1.0-2.0] in the SPH group vs 2.5 years [1.5-3.0] in the non-SPH group, P = .014). When comparing their biochemical evaluation, patients with SPH had higher levels of morning adrenocorticotropin (ACTH) (60.8 pg/mL [43.5-80.3]) compared to patients without SPH (39.4 pg/mL [28.2-53.2], P = .016) and the degree of cortisol reduction after overnight high dose (8 mg or weight-based equivalent) dexamethasone was lower (-58.0% [-85.4 to -49.7]) compared to patients without SPH (85.8 [-90.5 to -76.8], P = .035). The presence of SPH did not affect the odds of remission after surgery or the risk of recurrence after initial remission.ConclusionSPH in ACTH-secreting pituitary adenomas may affect their biochemical response during endocrine evaluations. They may, for example, fail to suppress to dexamethasone which can complicate diagnosis. Thus, SPH should be mentioned on imaging and taken into consideration in the work up of pediatric patients with CD.
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