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.

Programmed cell senescence: role of IL-6 in the pituitary

“…Taking into account that IL-6 participates in the progression of pituitary tumors, and its role in OIS, this cytokine appears as a candidate for an autocrine/paracrine regulator of pituitary adenoma control. The regulation of OIS by IL-6 has been recently shown using a pituitary tumor senescence cell model (MtT/S cell line) and an in vivo senescence model in human pituitary tumor samples (Sapochnik et al 2016). In both models, the absence of endogenous IL-6 produces a decrease in senescent biomarkers and, as expected, an increase in cell proliferation and invasion capacity.…”

“…OIS has been implicated in the arrest of pituitary tumors as in several other types of benign tumors. It has been shown in human and murine melanocytic nevi (Michaloglou et al 2005, Goel et Alexandraki et al 2012, Sapochnik et al 2016), but not in malignant adenocarcinomas. Cell senescence has a functional relevance in vivo, as a physiological mechanism limiting tumorigenesis in many diseases.…”

“…IL-6 mRNA and protein levels were also detected in cell cultures of all types of pituitary adenomas (Jones et al 1994, Borg et al 2003, Sapochnik et al 2016. Pituitary IL-6 production can be increased by many compounds such as IL-1 (Spangelo et al 1991), TNFα, pituitary adenylate cyclase-activating polypeptide and by lipopolysaccharides (Tichomirowa et al 2005), and it is inhibited by glucocorticoids .…”

“…Certainly, the secretory profile and function of the SASP are highly dependent on the cell type and context. Besides its paracrine mitogenic action, IL-6 was shown to actively contribute to the senescence process by reinforcing cell-cycle arrest in an autocrine feedback loop: is required for the execution of OIS in a cell-autonomous mode (Kuilman et al 2008, Sapochnik et al 2016). IL-6 depletion causes the inflammatory network to collapse and abolishes senescence entry and maintenance.…”

“…Pituitary tumorigenesis appears to be regulated by extrinsic and intrinsic factors. It has been demonstrated that paracrine IL-6's effects may allow initial pituitary cell growth (required for senescence bypass) , Arzt 2001, Graciarena et al 2004, whereas autocrine IL-6 in the same tumor triggers senescence and restrains aggressive growth and malignant transformation (Sapochnik et al 2016). This review provides an insight into the current understanding of the role of IL-6 in the regulation of pituitary pathogenesis, focusing in the autocrine action of IL-6.…”