Evidence of cellular senescence program as a pituitary tumoral suppressive mechanism

ANA LUCIA DE PAUL

Mar del Plata

Simposio; REUNIÓN ANUAL DE SOCIEDADES DE BIOCIENCIA 2019; 2019

Sociedad Argentina de Investigación Clínica (SAIC)

Pituitary tumours are usually benign neoplasms, represent 25% of intracranial lesions and rarely undergo malignant transformations, with the latter occurring in around 0.2% of all clinical cases. Recent findings have associated premature cell senescence with the features of pituitary adenomas, a process conceived as a tumoral suppressive mechanism. In this study, we investigated the emergence of cellular senescence and the mitochondrial adaptive shift during in vivo development of experimental pituitary tumours. The quantification of Ki67-immunopositive cells in the pituitaries derived from estrogenized male rats (10, 20, 40, and 60 days) revealed that the mitogenic potential rate was not sustained for the whole period analyzed and successively decreased after 10 days of estrogen exposure. In addition, the progressive rise in the SA-b-gal activity, IL6, IL1b, and TGFb expression, was observed throughout the pituitary tumour development. Furthermore, tumoral cells also displayed nuclear pATM protein expression, indicating activated DNA damage signalling, with a significant increase in p21 expression also being detected. We also showed clear evidence of oxidative stress in tumoral cells, associated with augmented mitochondrial biogenesis and an increased fusion process. Nrf2 stress response pathway activation together with the attenuation of the oxidative damage occurring during tumoral development were also detected. Moreover, the progressive increase in lactate production suggested a metabolic shift towards glycolysis metabolism. Our data indicate that cellular senescence should be conceived as a contributing component to the benign nature of pituitary adenomas, thereby influencing the capability of the pituitary gland to avoid unregulated cell proliferation. Additionally, the results helped us to reach an overview of the progressive mitochondrial switches needed for the survival of pituitary cells in order to cope with the damage in the context of tumoral development.