RESUMEN
Although effective treatment regimens (surgical resection, drug treatment with dopamine agonists or somatostatin analogues, radiotherapy) have been established for the therapy of most pituitary tumours, a considerable proportion of affected patients cannot completely cured due to incomplete resection or drug resistance. Moreover, even if hormone levels have been normalized, patients with hormone-secreting tumours still show persistent pathophysiological alterations in metabolic, cardiovascular or neuropsychiatric parameters and have an impaired quality of life. In this review reasons for the discrepancy between biochemical cure and incomplete recovery from tumour-associated comorbidities are discussed and the clinical management is delineated exemplarily for patients with acromegaly and Cushing's disease. In view of the development of additional treatment concepts for the treatment of pituitary adenomas we speculate about the relevance of RSUME as a potential target for the development of an anti-angiogenic therapy. Moreover, the role of BMP-4 which stimulates prolactinoma development through the Smad signalling cascade is described and its role as putative drug target for the treatment of prolactinomas is discussed. Regarding the well-known resistance of a part of somatotropinomas to somatostatin analogue treatment, recently identified mechanisms responsible for the drug resistance are summarized and ways to overcome them in future treatment concepts are presented. Concerning novel therapeutic options for patients with Cushing's disease the impact of retinoic acid, which is currently tested in clinical studies, is shown, and the action and putative therapeutic impact of silibinin to resolve glucocorticoid resistance in these patients is critically discussed.
Asunto(s)
Neoplasias Hipofisarias/tratamiento farmacológico , Investigación Biomédica Traslacional/métodos , Animales , Humanos , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/tratamiento farmacológico , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/fisiopatología , Neoplasias Hipofisarias/fisiopatología , Prolactinoma/tratamiento farmacológico , Prolactinoma/fisiopatología , Calidad de Vida , Somatostatina/análogos & derivados , Somatostatina/uso terapéuticoRESUMEN
PURPOSE: Somatostatin analogues (SSA) are efficacious and safe treatments for a variety of neuroendocrine tumors, especially pituitary neuroendocrine tumors (PitNET). Their therapeutic effects are mainly mediated by somatostatin receptors SST2 and SST5. Most SSAs, such as octreotide/lanreotide/pasireotide, are either nonselective or activate mainly SST2. However, nonfunctioning pituitary tumors (NFPTs), the most common PitNET type, mainly express SST3 and finding peptides that activate this particular somatostatin receptor has been very challenging. Therefore, the main objective of this study was to identify SST3-agonists and characterize their effects on experimental NFPT models. EXPERIMENTAL DESIGN: Binding to SSTs and cAMP level determinations were used to screen a peptide library and identify SST3-agonists. Key functional parameters (cell viability/caspase activity/chromogranin-A secretion/mRNA expression/intracellular signaling pathways) were assessed on NFPT primary cell cultures in response to SST3-agonists. Tumor growth was assessed in a preclinical PitNET mouse model treated with a SST3-agonist. RESULTS: We successfully identified the first SST3-agonist peptides. SST3-agonists lowered cell viability and chromogranin-A secretion, increased apoptosis in vitro, and reduced tumor growth in a preclinical PitNET model. As expected, inhibition of cell viability in response to SST3-agonists defined two NFPT populations: responsive and unresponsive, wherein responsive NFPTs expressed more SST3 than unresponsive NFPTs and exhibited a profound reduction of MAPK, PI3K-AKT/mTOR, and JAK/STAT signaling pathways upon SST3-agonist treatments. Concurrently, SSTR3 silencing increased cell viability in a subset of NFPTs. CONCLUSIONS: This study demonstrates that SST3-agonists activate signaling mechanisms that reduce NFPT cell viability and inhibit pituitary tumor growth in experimental models that expresses SST3, suggesting that targeting this receptor could be an efficacious treatment for NFPTs.
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Tumores Neuroendocrinos/tratamiento farmacológico , Péptidos/farmacología , Neoplasias Hipofisarias/tratamiento farmacológico , Receptores de Somatostatina/agonistas , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Quinasas Janus/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/patología , Péptidos/química , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias Hipofisarias/metabolismo , Neoplasias Hipofisarias/patología , Transducción de Señal , Células Tumorales Cultivadas , Adulto JovenRESUMEN
Poor sleep hygiene is a growing problem, with detrimental effects on many biological systems. The pituitary gland plays a crucial role in the regulation of sleep and the stress response, and its dysfunction leads to sleep-related disorders. However, the interaction between these critical functions remains unclear. Thus, we performed a comparative, whole-transcriptome, analysis to identify stress-induced genes and relevant pathways that may be affected by sleep deprivation. One day following 12 h of Paradoxical Sleep Deprivation (PSD), mice were restrained for 20 min. Gene expression changes in the pituitary were assessed via RNA-Seq and Gene Ontology in PSD and/or restrained groups compared to controls. We show that restraint triggers transcriptional responses involved in hormone secretion, the glucocorticoid response, and apoptosis in both sexes, with 285 differentially expressed genes in females and 93 in males. When PSD preceded restraint stress, the numbers of differentially expressed genes increased to 613 in females and 580 in males. The pituitary transcriptome of restraint+PSD animals was enriched for microglia and macrophage proliferation, cellular response to corticosteroids, and apoptosis, among others. Finally, we identify sex-specific differences in restraint-induced genes following PSD. These findings provide genetic targets to consider when studying sleep and the response to stress.
RESUMEN
BACKGROUND: Cushing's disease (CD) is caused by adrenocorticotropic hormone (ACTH)-secreting pituitary tumours. They express high levels of heat shock protein 90 and heat shock factor 1 (HSF1) in comparison to the normal tissue counterpart, indicating activated cellular stress. AIMS: Our objectives were: (1) to correlate HSF1 expression with clinical features and hormonal/radiological findings of CD, and (2) to investigate the effects of HSF1 inhibition as a target for CD treatment. PATIENTS/METHODS: We examined the expression of total and pSer326HSF1 (marker for its transcriptional activation) by Western blot on eight human CD tumours and compared to the HSF1 status of normal pituitary. We screened a cohort of 45 patients with CD for HSF1 by immunohistochemistry and correlated the HSF1 immunoreactivity score with the available clinical data. We evaluated the effects of HSF1 silencing with RNA interference and the HSF1 inhibitor KRIBB11 in AtT-20 cells and four primary cultures of human corticotroph tumours. RESULTS: We show that HSF1 protein is highly expressed and transcriptionally active in CD tumours in comparison to normal pituitary. The immunoreactivity score for HSF1 did not correlate with the typical clinical features of the disease. HSF1 inhibition reduced proopiomelanocortin (Pomc) transcription in AtT-20 cells. The HSF1 inhibitor KRIBB11 suppressed ACTH synthesis from 75% of human CD tumours in primary cell culture. This inhibitory action on Pomc transcription was mediated by increased glucocorticoid receptor and suppressed Nurr77/Nurr1 and AP-1 transcriptional activities. CONCLUSIONS: These data show that HSF1 regulates POMC transcription. Pharmacological targeting of HSF1 may be a promising treatment option for the control of excess ACTH secretion in CD.
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Factores de Transcripción del Choque Térmico/antagonistas & inhibidores , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/tratamiento farmacológico , Proopiomelanocortina/biosíntesis , Proopiomelanocortina/genética , Hormona Adrenocorticotrópica/biosíntesis , Adulto , Aminopiridinas/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Silenciador del Gen , Factores de Transcripción del Choque Térmico/genética , Humanos , Inmunohistoquímica , Indazoles/farmacología , Masculino , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/metabolismo , Interferencia de ARN , Factor de Transcripción AP-1/farmacología , Activación Transcripcional/efectos de los fármacos , Adulto JovenRESUMEN
The co-chaperone FKBP5 is a stress-responsive protein-regulating stress reactivity, and its genetic variants are associated with T2D related traits and other stress-related disorders. Here we show that FKBP51 plays a role in energy and glucose homeostasis. Fkbp5 knockout (51KO) mice are protected from high-fat diet-induced weight gain, show improved glucose tolerance and increased insulin signaling in skeletal muscle. Chronic treatment with a novel FKBP51 antagonist, SAFit2, recapitulates the effects of FKBP51 deletion on both body weight regulation and glucose tolerance. Using shorter SAFit2 treatment, we show that glucose tolerance improvement precedes the reduction in body weight. Mechanistically, we identify a novel association between FKBP51 and AS160, a substrate of AKT2 that is involved in glucose uptake. FKBP51 antagonism increases the phosphorylation of AS160, increases glucose transporter 4 expression at the plasma membrane, and ultimately enhances glucose uptake in skeletal myotubes. We propose FKBP51 as a mediator between stress and T2D development, and potential target for therapeutic approaches.
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Proteínas Activadoras de GTPasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas de Unión a Tacrolimus/metabolismo , Animales , Transporte Biológico Activo , Dieta Alta en Grasa , Glucosa/metabolismo , Transportador de Glucosa de Tipo 4/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Biológicos , Fibras Musculares Esqueléticas/metabolismo , Fosforilación , Transducción de Señal , Estrés Fisiológico , Proteínas de Unión a Tacrolimus/deficiencia , Proteínas de Unión a Tacrolimus/genética , Aumento de PesoRESUMEN
INTRODUCTION: Cushing's disease (CD) is caused by a corticotroph adenoma of the pituitary gland that secretes excess adrenocorticotropic hormone (ACTH) causing increased morbidity and mortality. Surgery is the treatment of choice, but is not always successful. Alternatives include radiotherapy, adrenal surgery, and pharmaceutical therapy. The latter is increasingly gaining momentum due to the recent development of compounds that reduce hypercortisolaemia or its symptoms, acting through different mechanisms. Areas covered: In this article, the authors provide a complete overview of the treatment options for Cushing´s disease, including adrenal-directed, tumor-targeted, and peripheral therapies that are currently used or in development, and discuss their potential advantages and limitations. Expert opinion: Considering the lack of long-term remission in up to half of the patients after surgery, and the delayed response to radiotherapy along with potential side effects, there is a strong need for an effective pharmaceutical treatment. Pasireotide, mifepristone, ketoconazole and metyrapone have been approved by regulatory authorities but their use remains limited due to considerable costs and side effects. Research in this field has focused recently on the improvement of pre-existing drugs and the development of safe new ones. However, few approaches aim at targeting the source of the disease, the ACTH-secreting adenoma.
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Diseño de Fármacos , Drogas en Investigación/uso terapéutico , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/tratamiento farmacológico , Adenoma Hipofisario Secretor de ACTH/complicaciones , Hormona Adrenocorticotrópica/metabolismo , Animales , Drogas en Investigación/efectos adversos , Drogas en Investigación/farmacología , Humanos , Terapia Molecular Dirigida , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/etiología , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/patologíaRESUMEN
The P2X7 receptor is a member of the P2X family of ligand-gated ion channels. A single-nucleotide polymorphism leading to a glutamine (Gln) by arginine (Arg) substitution at codon 460 of the purinergic P2X7 receptor (P2X7R) has been associated with mood disorders. No change in function (loss or gain) has been described for this SNP so far. Here we show that although the P2X7R-Gln460Arg variant per se is not compromised in its function, co-expression of wild-type P2X7R with P2X7R-Gln460Arg impairs receptor function with respect to calcium influx, channel currents and intracellular signaling in vitro. Moreover, co-immunoprecipitation and FRET studies show that the P2X7R-Gln460Arg variant physically interacts with P2X7R-WT. Specific silencing of either the normal or polymorphic variant rescues the heterozygous loss of function phenotype and restores normal function. The described loss of function due to co-expression, unique for mutations in the P2RX7 gene so far, explains the mechanism by which the P2X7R-Gln460Arg variant affects the normal function of the channel and may represent a mechanism of action for other mutations.
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Polimorfismo de Nucleótido Simple/genética , Receptores Purinérgicos P2X7/fisiología , Western Blotting , Calcio/metabolismo , Calcio/fisiología , Transferencia Resonante de Energía de Fluorescencia , Células HEK293 , Humanos , Inmunoprecipitación , Técnicas de Placa-Clamp , Polimorfismo de Nucleótido Simple/fisiología , ARN Interferente Pequeño/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores Purinérgicos P2X7/genética , Receptores Purinérgicos P2X7/metabolismo , Transducción de Señal/fisiologíaRESUMEN
Hypothalamic leptin signalling has a key role in food intake and energy-balance control and is often impaired in obese individuals. Here we identify histone deacetylase 5 (HDAC5) as a regulator of leptin signalling and organismal energy balance. Global HDAC5 KO mice have increased food intake and greater diet-induced obesity when fed high-fat diet. Pharmacological and genetic inhibition of HDAC5 activity in the mediobasal hypothalamus increases food intake and modulates pathways implicated in leptin signalling. We show HDAC5 directly regulates STAT3 localization and transcriptional activity via reciprocal STAT3 deacetylation at Lys685 and phosphorylation at Tyr705. In vivo, leptin sensitivity is substantially impaired in HDAC5 loss-of-function mice. Hypothalamic HDAC5 overexpression improves leptin action and partially protects against HFD-induced leptin resistance and obesity. Overall, our data suggest that hypothalamic HDAC5 activity is a regulator of leptin signalling that adapts food intake and body weight to our dietary environment.
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Hipotálamo/metabolismo , Leptina/metabolismo , Animales , Glucemia , Línea Celular , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Prueba de Tolerancia a la Glucosa , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Infusiones Intraventriculares , Resistencia a la Insulina , Captura por Microdisección con Láser , Leptina/genética , Masculino , Hormonas Estimuladoras de los Melanocitos/farmacología , Ratones , Ratones Endogámicos , Ratones Noqueados , Neuronas/fisiología , Ratas , Ratas WistarRESUMEN
One function of the glucocorticoid receptor (GR) in corticotroph cells is to suppress the transcription of the gene encoding proopiomelanocortin (POMC), the precursor of the stress hormone adrenocorticotropin (ACTH). Cushing disease is a neuroendocrine condition caused by partially glucocorticoid-resistant corticotroph adenomas that excessively secrete ACTH, which leads to hypercortisolism. Mutations that impair GR function explain glucocorticoid resistance only in sporadic cases. However, the proper folding of GR depends on direct interactions with the chaperone heat shock protein 90 (HSP90, refs. 7,8). We show here that corticotroph adenomas overexpress HSP90 compared to the normal pituitary. N- and C-terminal HSP90 inhibitors act at different steps of the HSP90 catalytic cycle to regulate corticotroph cell proliferation and GR transcriptional activity. C-terminal inhibitors cause the release of mature GR from HSP90, which promotes its exit from the chaperone cycle and potentiates its transcriptional activity in a corticotroph cell line and in primary cultures of human corticotroph adenomas. In an allograft mouse model, the C-terminal HSP90 inhibitor silibinin showed anti-tumorigenic effects, partially reverted hormonal alterations, and alleviated symptoms of Cushing disease. These results suggest that the pathogenesis of Cushing disease caused by overexpression of heat shock proteins and consequently misregulated GR sensitivity may be overcome pharmacologically with an appropriate HSP90 inhibitor.
Asunto(s)
Adenoma Hipofisario Secretor de ACTH/genética , Adenoma/genética , Resistencia a Medicamentos/genética , Regulación Neoplásica de la Expresión Génica , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/genética , Pliegue de Proteína/efectos de los fármacos , Receptores de Glucocorticoides/efectos de los fármacos , Silimarina/farmacología , Adenoma Hipofisario Secretor de ACTH/complicaciones , Adenoma/complicaciones , Aloinjertos , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/etiología , SilibinaRESUMEN
FK506-binding protein 51 (FKBP51) is a co-chaperone of the glucocorticoid receptor, functionally linked to its activity via an ultra-short negative feedback loop. Thus, FKBP51 plays an important regulatory role in the hypothalamic-pituitary-adrenocortical (HPA) axis necessary for stress adaptation and recovery. Previous investigations illustrated that HPA functionality is influenced by polymorphisms in the gene encoding FKBP51, which are associated with both increased protein levels and depressive episodes. Because FKBP51 is a key molecule in stress responses, we hypothesized that its deletion impacts sleep. To study FKBP51-involved changes in sleep, polysomnograms of FKBP51 knockout (KO) mice and wild-type (WT) littermates were compared at baseline and in the recovery phase after 6-h sleep deprivation (SD) and 1-h restraint stress (RS). Using another set of animals, the 24-h profiles of hippocampal free corticosterone levels were also determined. The most dominant effect of FKBP51 deletion appeared as increased nocturnal wake, where the bout length was significantly extended while non-rapid eye movement sleep (NREMS) and rapid eye movement sleep were rather suppressed. After both SD and RS, FKBP51KO mice exhibited less recovery or rebound sleep than WTs, although slow-wave activity during NREMS was higher in KOs, particularly after SD. Sleep compositions of KOs were nearly opposite to sleep profiles observed in human depression. This might result from lower levels of free corticosterone in FKBP51KO mice, confirming reduced HPA reactivity. The results indicate that an FKBP51 deletion yields a pro-resilience sleep phenotype. FKBP51 could therefore be a therapeutic target for stress-induced mood and sleep disorders.
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Privación de Sueño/metabolismo , Privación de Sueño/fisiopatología , Sueño , Proteínas de Unión a Tacrolimus/metabolismo , Animales , Corticosterona/sangre , Trastorno Depresivo/metabolismo , Humanos , Sistema Hipotálamo-Hipofisario/metabolismo , Masculino , Ratones , Ratones Noqueados , Sistema Hipófiso-Suprarrenal/metabolismo , Polimorfismo Genético , Polisomnografía , Privación de Sueño/sangre , Trastornos del Sueño-Vigilia/metabolismo , Trastornos del Sueño-Vigilia/fisiopatología , Sueño REM , Proteínas de Unión a Tacrolimus/deficiencia , Proteínas de Unión a Tacrolimus/genéticaRESUMEN
RSUME (RWD-containing SUMO Enhancer) is a small protein that increases SUMO conjugation to proteins. To date, four splice variants that codify three RSUME isoforms have been described, which differ in their C-terminal end. Comparing the structure of the RSUME isoforms we found that, in addition to the previously described RWD domain in the N-terminal, all these RSUME variants also contain an intermediate domain. Only the longest RSUME isoform presents a C-terminal domain that is absent in the others. Given these differences, we used the shortest and longest RSUME variants for comparative studies. We found that the C-terminal domain is dispensable for the SUMO-conjugation enhancer properties of RSUME. We also demonstrate that these two RSUME variants are equally induced by hypoxia. The NF-κB signaling pathway is inhibited and the HIF-1 pathway is increased more efficiently by the longest RSUME, by means of a greater physical interaction of RSUME267 with the target proteins. In addition, the mRNA and protein levels of these isoforms differ in human glioma samples; while the shortest RSUME isoform is expressed in all the tumors analyzed, the longest variant is expressed in most but not all of them. The results presented here show a degree of redundancy of the RSUME variants on the SUMO pathway. However, the increased inhibition conferred by RSUME267 over the NF-κB signaling pathway, the increased activation over the HIF-1 pathway and the different expression of the RSUME isoforms suggest specific roles for each RSUME isoform which may be relevant in certain types of brain tumors that express RSUME, like human pituitary adenomas and gliomas.
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Biología Computacional , Factores de Transcripción/química , Factores de Transcripción/metabolismo , Secuencia de Aminoácidos , Animales , Línea Celular , Regulación de la Expresión Génica , Humanos , Factor 1 Inducible por Hipoxia/metabolismo , Modelos Moleculares , Datos de Secuencia Molecular , FN-kappa B/metabolismo , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Estructura Secundaria de Proteína , Proteína SUMO-1/metabolismo , Transducción de Señal , Factores de Transcripción/genéticaRESUMEN
Glucocorticoid receptor (GR) activity is modulated by posttranslational modifications, including phosphorylation, ubiquitination, and SUMOylation. The GR has three SUMOylation sites: lysine 297 (K297) and K313 in the N-terminal domain (NTD) and K721 within the ligand-binding domain. SUMOylation of the NTD sites mediates the negative effect of the synergy control motifs of GR on promoters with closely spaced GR binding sites. There is scarce evidence on the role of SUMO conjugation to K721 and its impact on GR transcriptional activity. We have previously shown that RSUME (RWD-containing SUMOylation enhancer) increases protein SUMOylation. We now demonstrate that RSUME interacts with the GR and increases its SUMOylation. RSUME regulates GR transcriptional activity and the expression of its endogenous target genes, FKBP51 and S100P. RSUME uncovers a positive role for the third SUMOylation site, K721, on GR-mediated transcription, demonstrating that GR SUMOylation acts positively in the presence of a SUMOylation enhancer. Both mutation of K721 and small interfering RNA-mediated RSUME knockdown diminish GRIP1 coactivator activity. RSUME, whose expression is induced under stress conditions, is a key factor in heat shock-induced GR SUMOylation. These results show that inhibitory and stimulatory SUMO sites are present in the GR and at higher SUMOylation levels the stimulatory one becomes dominant.
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Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Factores de Transcripción/metabolismo , Animales , Arginina/genética , Células COS , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Línea Celular , Chlorocebus aethiops , Respuesta al Choque Térmico/fisiología , Mutación , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Estructura Terciaria de Proteína , Ratas , Sumoilación , Factores de Transcripción/genética , Activación TranscripcionalRESUMEN
Growth hormone (GH) is a major anabolic hormone and the primary regulator of organism growth. Its transcription is triggered by GH-releasing hormone (GHRH) through the transcription factor cAMP response element-binding protein (CREB) and by caloric intake. In contrast, the deacetylase Sirt1 is activated by caloric restriction. Therefore, the present study investigates how Sirt1 affects CREB function and GH synthesis. Sirt1 pharmacological activation with resveratrol (IC50=87 µM) suppressed GHRH-induced GH secretion from rat anterior pituitary cells in vivo and in vitro, while vehicle controls showed no effect. Resveratrol's effects were abolished after knocking down Sirt1 with RNA interference, but not in control scrambled siRNA-transfected rat somatotrophs, confirming the Sirt1 specificity. Sirt1 activation and overexpression suppressed forskolin-induced CREB-Ser(133) phosphorylation, but no effect was seen with vehicle and empty plasmid controls. The deacetylase-dead mutant Sirt1 retained CREB-Ser(133) phosphorylation by keeping protein phosphatase protein phosphatase 1 activity low. Sirt1 activation suppressed glycogen synthase kinase 3 ß acetylation, and a mutation on the GSK3ß-Lys(205) residue mimicking a hypoacetylated form revealed increased activity. In summary, this is a novel mechanism through which Sirt1 intercepts the cAMP pathway by suppressing CREB transcriptional activation, resulting in decreased GH synthesis.
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Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Hormona del Crecimiento/biosíntesis , Sirtuina 1/metabolismo , Animales , Colforsina/farmacología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Hormona del Crecimiento/genética , Hormona Liberadora de Hormona del Crecimiento/genética , Hormona Liberadora de Hormona del Crecimiento/metabolismo , Masculino , Adenohipófisis/efectos de los fármacos , Adenohipófisis/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Hormona Reguladora de Hormona Hipofisaria/genética , Receptores de Hormona Reguladora de Hormona Hipofisaria/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Activación Transcripcional/fisiologíaRESUMEN
The FK506 binding protein 51 (FKBP51) is best known as an Hsp90-associated co-chaperone that regulates the responsiveness of steroid hormone receptors. In human genetic association studies, FKBP51 has repeatedly been associated with emotion processing and numerous stress-related affective disorders. It has also been implicated in contributing to the glucocorticoid hyposensitivity observed in New World primates. More recently, several research groups have consistently shown a protective effect of FKBP51 knockout or knockdown on stress endocrinology and stress-coping behavior in animal models of depression and anxiety. The principal druggability of FKBP51 is exemplified by the prototypic FKBP ligands FK506 and rapamycin. Moreover, FKBP51 is highly suited for X-ray co-crystallography, which should facilitate the rational drug design of improved FKBP51 ligands. In summary, FKBP51 has emerged as a promising new drug target for stress-related disorders that should be amenable to drug discovery.
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Proteínas de Unión a Tacrolimus/antagonistas & inhibidores , Animales , Antidepresivos/uso terapéutico , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/metabolismo , Diseño de Fármacos , Metabolismo Energético , Técnicas de Silenciamiento del Gen , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Ligandos , Ratones , Ratones Noqueados , Polimorfismo de Nucleótido Simple , Receptores de Esteroides/metabolismo , Proteínas de Unión a Tacrolimus/genética , Proteínas de Unión a Tacrolimus/metabolismoRESUMEN
INTRODUCTION: Major depressive disorder is a serious and common psychiatric illness, and many of the depressive patients benefit from pharmacological treatment. Available antidepressants produce remission in only about 30 -- 40% of the patients. Therefore, new concepts are being explored for the development of innovative antidepressants with higher efficacy. AREAS COVERED: The use of corticotropin releasing factor type 1 (CRF1) receptor antagonists for depression is supported by abundant evidence of target validation, the availability of in vitro and in vivo assays and specific small ligands. Some of these compounds have advanced to clinical studies, with discouraging results so far in depression. This review covers the development of CRF1 receptor antagonists at different stages of the development pipeline of the pharmaceutical industry and its bottlenecks. Most of the available CRF1 receptor antagonists known so far share a common chemical scaffold. We present possible strategies to overcome obstacles in the discovery and development process at the levels of library screenings and clinical studies to find more diverse compounds. EXPERT OPINION: CRF1 receptor antagonists are expected to be beneficial only for those patients with CRF overexpression and the need for tests to identify these individuals is discussed. New technical developments and diagnostic tools might eventually lead to a more successful treatment of major depression with CRF1 receptor antagonists.
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Antidepresivos/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Drogas en Investigación/uso terapéutico , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Animales , Antidepresivos/farmacología , Ensayos Clínicos como Asunto , Hormona Liberadora de Corticotropina/fisiología , Trastorno Depresivo Mayor/complicaciones , Sistemas de Liberación de Medicamentos/métodos , Descubrimiento de Drogas/métodos , Drogas en Investigación/farmacología , Humanos , Medicina de Precisión/métodos , Estrés Psicológico/complicaciones , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/fisiopatologíaRESUMEN
Cytokines of the IL-6 or gp130 family regulate many cellular responses and play regulatory roles in numerous tissues, and are placed as auto-paracrine regulators of pituitary function acting in normal and tumoral anterior pituitary cells. Especially, IL-6 has a regulatory role in the hormone secretion and growth of the anterior pituitary and is involved in adenoma pathogenesis. Recently, IL-6 has been shown to mediate oncogene-induced senescence (OIS). IL-6 might participate in such a process in adenomas pituitary as well. From pituitary tumoral gp130 overexpressing cells, an unknown protein, RSUME, has been cloned. RSUME is induced by hypoxia in pituitary tumors and regulate pathways involved in angiogenic and tumorigenic processes (NF-kappaB/IkappaB and HIF-1alpha pathways). Thus, it could have an important role in the development of the pituitary tumors.
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Receptor gp130 de Citocinas/fisiología , Interleucina-6/fisiología , Neoplasias Hipofisarias/etiología , Factores de Transcripción/fisiología , Animales , Perfilación de la Expresión Génica , HumanosRESUMEN
BMP-4 plays a crucial role not only in the formation of the anterior pituitary during embryo development but also in the pathogenesis of pituitary tumors in adults. In tumor cells, BMP-4 promotes prolactin secretion and lactotroph cell proliferation through a Smad-estrogen receptor crosstalk but it inhibits ACTH production and cell proliferation of corticotrophs. In addition, BMP-4 increases GH secretion in rat pituitary tumor somatolactotroph GH3 cells and FSHbeta subunit gene transcription in the murine gonadotroph cell line, LbetaT2. Therefore, BMP-4 has a differential role on different types of pituitary tumors: it promotes pituitary prolactinoma while it inhibits corticotroph pathogenesis in Cushing's disease. The modulation of BMP-4 also plays an important role in the therapeutic mechanism of action of bromocriptine, somatostatin analogs and retinoic acid.
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Proteína Morfogenética Ósea 4/fisiología , Neoplasias Hipofisarias/etiología , Hormona Adrenocorticotrópica/metabolismo , Adulto , Animales , Proteína Morfogenética Ósea 4/metabolismo , Proteínas Morfogenéticas Óseas/metabolismo , Humanos , Ratones , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/complicaciones , Hipófisis/embriología , Hipófisis/patología , Neoplasias Hipofisarias/metabolismo , Prolactina/metabolismo , Prolactinoma/metabolismo , RatasRESUMEN
Rapamycin and its analogues have significant antiproliferative action against a variety of tumors. However, sensitivity to rapamycin is reduced by Akt activation that results from the ablative effects of rapamycin on a p70 S6K-induced negative feedback loop that blunts phosphoinositide 3-kinase (PI3K)-mediated support for Akt activity. Thus, sensitivity to rapamycin might be increased by imposing an upstream blockade to the PI3K/Akt pathway. Here, we investigated this model using the somatostatin analogue octreotide as a tool to decrease levels of activated Ser(473)-phosphorylated Akt (pAkt-Ser(473)) in pituitary tumor cells that express somatostatin receptors. Octreotide increased levels of phosphorylated insulin receptor substrate-1 that were suppressed by rapamycin, subsequently decreasing levels of pAkt-Ser(473) through effects on phosphotyrosine phosphatase SHP-1. Octreotide potentiated the antiproliferative effects of rapamycin in immortalized pituitary tumor cells or human nonfunctioning pituitary adenoma cells in primary cell culture, sensitizing tumor cells even to low rapamycin concentrations. Combined treatment of octreotide and rapamycin triggered G(1) cell cycle arrest, decreasing E2F transcriptional activity and cyclin E levels by increasing levels of p27/Kip1. These findings show that adjuvant treatment with a somatostatin analogue can sensitize pituitary tumor cells to the antiproliferative effects of rapamycin.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Octreótido/farmacología , Neoplasias Hipofisarias/tratamiento farmacológico , Sirolimus/farmacología , Adenoma/tratamiento farmacológico , Adenoma/metabolismo , Adenoma/patología , Ciclo Celular/efectos de los fármacos , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/biosíntesis , Sinergismo Farmacológico , Humanos , Proteínas Sustrato del Receptor de Insulina/metabolismo , Octreótido/administración & dosificación , Proteína Oncogénica v-akt/metabolismo , Fosforilación/efectos de los fármacos , Neoplasias Hipofisarias/metabolismo , Neoplasias Hipofisarias/patología , Sirolimus/administración & dosificación , Sirolimus/antagonistas & inhibidores , Regulación hacia ArribaRESUMEN
Research performed on the pituitary has proven that cytokines play an important role in maintaining pituitary physiology, affecting not only cell proliferation but also hormone secretion. The effects of cytokines can be autocrine or paracrine. This review gives an overview on the effects of the most studied cytokines in the pituitary. Special interest is focused on interleukin-6 (IL-6) because it has the distinctive characteristic of stimulating pituitary tumor cell growth, but has the opposite effect on normal pituitary cells. On the other hand, IL-6 is a cytokine of interest in the pituitary because recent work has shown that it promotes and maintains senescence in certain types of tumors. Given that the majority of pituitary adenomas are microadenomas and the fact that clinically inapparent pituitary tumors are quite common, senescence, perhaps mediated by IL-6, is an attractive mechanism for explaining the benign nature of pituitary tumors.