title: Autocrine IL-6 mediates pituitary tumor senescence.
abstract: 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-β-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-β-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.
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA)-CONICET-Partner Institute of the Max Planck Society, Buenos Aires, C1425FQD, Argentina.
authors.forename: Melanie
authors.initials: M
authors.lastname: Sapochnik
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA)-CONICET-Partner Institute of the Max Planck Society, Buenos Aires, C1425FQD, Argentina.
authors.forename: Mariana R
authors.initials: MR
authors.lastname: Haedo
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA)-CONICET-Partner Institute of the Max Planck Society, Buenos Aires, C1425FQD, Argentina.
authors.forename: Mariana
authors.initials: M
authors.lastname: Fuertes
authors.affiliation: Servicio de Neurocirugía, Hospital Italiano, C1199ABD, Buenos Aires, Argentina.
authors.forename: Pablo
authors.initials: P
authors.lastname: Ajler
authors.affiliation: Servicio de Neurocirugía, Hospital Italiano, C1199ABD, Buenos Aires, Argentina.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Carrizo
authors.affiliation: Departamento de Neurocirugía, Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI), C1428AQK, Buenos Aires, Argentina.
authors.forename: Andrés
authors.initials: A
authors.lastname: Cervio
authors.affiliation: Departamento de Neurocirugía, Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI), C1428AQK, Buenos Aires, Argentina.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Sevlever
authors.affiliation: Department of Clinical Research, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Günter K
authors.initials: GK
authors.lastname: Stalla
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA)-CONICET-Partner Institute of the Max Planck Society, Buenos Aires, C1425FQD, Argentina.|Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, C1428EGA, Argentina.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Arzt
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D010911:Pituitary Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016160:Retinoblastoma Protein / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C508600:IL6 protein, human; D015850:Interleukin-6; D016160:Retinoblastoma Protein; D001616:beta-Galactosidase
keywords: IL-6; autocrine; benign tumor; pituitary tumor; senescence