RESUMEN
Cellular senescence is a stable proliferative arrest state. Pituitary adenomas are frequent and mostly benign, but the mechanism for this remains unknown. IL-6 is involved in pituitary tumor progression and is produced by the tumoral cells. In a cell autonomous fashion, IL-6 participates in oncogene-induced senescence in transduced human melanocytes. Here we prove that autocrine IL-6 participates in pituitary tumor senescence. Endogenous IL-6 inhibition in somatotroph MtT/S shRNA stable clones results in decreased SA-ß-gal activity and p16INK4a but increased pRb, proliferation and invasion. Nude mice injected with IL-6 silenced clones develop tumors contrary to MtT/S wild type that do not, demonstrating that clones that escape senescence are capable of becoming tumorigenic. When endogenous IL-6 is silenced, cell cultures derived from positive SA-ß-gal human tumor samples decrease the expression of the senescence marker. Our results establish that IL-6 contributes to maintain senescence by its autocrine action, providing a natural model of IL-6 mediated benign adenoma senescence.
Asunto(s)
Comunicación Autocrina , Interleucina-6/genética , Interleucina-6/metabolismo , Neoplasias Hipofisarias/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular , Senescencia Celular , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Humanos , Ratones , Ratones Desnudos , Invasividad Neoplásica , Trasplante de Neoplasias , Fosforilación , Neoplasias Hipofisarias/genética , Neoplasias Hipofisarias/patología , Proteína de Retinoblastoma/metabolismo , beta-Galactosidasa/metabolismoRESUMEN
The anterior pituitary gland has the ability to respond to complex signals derived from central and peripheral systems. Perception of these signals and their integration are mediated by cell interactions and cross-talk of multiple signaling transduction pathways and transcriptional regulatory networks that cooperate for hormone secretion, cell plasticity, and ultimately specific pituitary responses that are essential for an appropriate physiological response. We discuss the physiopathological and molecular mechanisms related to this integrative regulatory system of the anterior pituitary gland and how it contributes to modulate the gland functions and impacts on body homeostasis.
Asunto(s)
Comunicación Celular/fisiología , Hipófisis/citología , Hipófisis/fisiología , Transducción de Señal/fisiología , Animales , Sistema Endocrino/fisiología , Homeostasis/fisiología , Hormonas/metabolismo , Humanos , Sistemas Neurosecretores/fisiologíaRESUMEN
SOM230 (pasireotide) is a multiligand somatostatin (SRIF) analog able to bind to somatostatin receptor (SSTR) subtypes 1, 2, 3 and 5, and trigger antisecretory and antiproliferative signaling cascades. Canines have become in vivo models to test the pharmacological treatment of corticotropinomas because they frequently develop Cushing's disease in a spontaneous manner, due to adrenocorticotropic hormone (ACTH)-producing pituitary adenomas. Different levels of expression of SSTR2 and SSTR5 have been shown in both mouse AtT20 cells and canine tumoral corticotropinoma cells. The objective of this study was to evaluate whether SOM230 controls both tumor cell growth and hormone synthesis, therefore controlling the disease. SOM230 was tested in dogs suffering from Cushing's disease (10 animals were treated continuously during 6 months, and another 10 were treated with 3 cycles consisting of 2 months of treatment followed by a 2-month rest period). A significant decrease in ACTH, urinary cortisol creatinine ratio, adenoma size (magnetic nuclear resonance) and improvement of clinical signs were obtained, without side effects. AtT20 cells treated with SOM230 suppressed pro-opiomelanocortin (POMC) promoter activity through SSTR2, via the G(i) α-subunit, and reduced Nur77/Nurr1 transcriptional activity. We conclude that SOM230, in addition to its well-described antisecretory effects, inhibits, as shown in AtT20 cells, ACTH synthesis at the POMC transcriptional level, an effect mediated mainly through SSTR2, and limits tumor growth. The controlled Cushing's disease in the dogs that received the treatment indicates that SOM230 has a potential therapeutic use in humans suffering from Cushing's disease.
Asunto(s)
Hormona Adrenocorticotrópica/biosíntesis , Corticotrofos/efectos de los fármacos , Corticotrofos/metabolismo , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/metabolismo , Somatostatina/análogos & derivados , Hormona Adrenocorticotrópica/sangre , Alanina Transaminasa/sangre , Fosfatasa Alcalina/sangre , Animales , Aspartato Aminotransferasas/sangre , Glucemia/metabolismo , Línea Celular Tumoral , Colesterol/sangre , Creatinina/orina , Perros , Femenino , Hidrocortisona/orina , Pruebas de Función Hepática , Imagen por Resonancia Magnética , Masculino , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/patología , Somatostatina/farmacología , Triglicéridos/sangre , alfa-MSH/sangreRESUMEN
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.