Autocrine IL-6 mediates pituitary tumor senescence.

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

doi:10.18632/oncotarget.13577

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.

Highlights

Cellular senescence is a state of stable proliferative arrest in G1 phase of the cell cycle through activation of the p53/p21Cip1 and pRb/p16INK4a signaling pathways, including alterations in the phenotype of the cells
These findings indicate that the somatotrophic MtT/S cell line presents senescent features
It has been observed that the mouse pituitary gonadotroph cell line LβT2 presents some senescent features which were increased by the overexpression of PTTG [41]

Summary

Introduction

Cellular senescence is a state of stable proliferative arrest in G1 phase of the cell cycle through activation of the p53/p21Cip1 and pRb/p16INK4a signaling pathways, including alterations in the phenotype of the cells. 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 findings show that the rat somatotroph cell line MtT/S presents a senescent phenotype, and constitutes an interesting model of pituitary tumor senescence.

Results

Conclusion