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Autocrine IL-6 mediates pituitary tumor senescence

2016; Impact Journals LLC; Volume: 8; Issue: 3 Linguagem: Inglês

10.18632/oncotarget.13577

1949-2553

Melanie Sapochnik, Mariana Haedo, Mariana Fuertes, Pablo Ajler, Guillermo Carrizo, Andrés Cervio, Gustavo Sevlever, Günter K. Stalla, Eduardo Arzt,

Retinoids in leukemia and cellular processes

// Melanie Sapochnik 1, * , Mariana R. Haedo 1, * , Mariana Fuertes 1 , Pablo Ajler 2 , Guillermo Carrizo 2 , Andrés Cervio 3 , Gustavo Sevlever 3 , Günter K. Stalla 4 , Eduardo Arzt 1, 5 1 Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA)-CONICET-Partner Institute of the Max Planck Society, Buenos Aires, C1425FQD, Argentina 2 Servicio de Neurocirugía, Hospital Italiano, C1199ABD, Buenos Aires, Argentina 3 Departamento de Neurocirugía, Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI), C1428AQK, Buenos Aires, Argentina 4 Department of Clinical Research, Max Planck Institute of Psychiatry, Munich, Germany 5 Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, C1428EGA, Argentina * These authors have contributed equally to this work Correspondence to: Eduardo Arzt, email: earzt@ibioba-mpsp-conicet.gov.ar Keywords: senescence, IL-6, pituitary tumor, benign tumor, autocrine Received: April 29, 2016 Accepted: November 06, 2016 Published: November 24, 2016 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 p16 INK4a 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.