Intracellular action of IL-6 in pituitary tumor senescence

SAPOCHNIK, M; ATTORRESI, A; FUERTES, M; PONTEL, L; HERBSTEIN, F; SENIN, S; ARZT, E

Mar del Plata

Congreso; LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica; 2019

Sociedad Argentina de Investigación Clínica

Pituitary adenomas are frequent, benign, non-metastatic and monoclonal tumors that have premature proliferative arrest. Senescence restrains proliferation, but allows the cell to remain viable and perform its physiological function. Oncogene induced senescence (OIS) represents a protective mechanism against potential oncogenic risks that can explain the benign nature of these tumors. It has been reported the role of interleukin 6 (IL-6) in the induction and maintenance of the OIS. In previous work we demonstrated that IL-6 contributes to maintain senescence by its autocrine action in a pituitary tumoral model. In order to determine the mechanisms that mediate the endogenous action of this cytokine we developed knock out (KO) clones with the CRISPR/Cas9 technology of IL-6 in the somatotrophic cell line MtT/S in which we proved the absence of protein expression through an ELISA assay in six clones. Two of these KO clones injected into NOD/SCID mice (four mice of each group) generated tumors 10 days after injection, unlike wild type (WT) cells that did not show tumor formation in vivo. We also observed that these KO clones had decreased senescence markers, p16INK4 and pRb. Contrary to WT cells in which inhibition of the secretion pathway with Brefeldin A (BFA) 100 ng/ml generated an increase in senescence markers and the activity of senescence-associated β-galactosidase (SA-β-Gal) (p