Response to estrogen- induced oxidative damage and alterations on mitochondrial dynamics in normal and tumoral pituitary cells

MONGI BRAGATO, B; DE PAUL, AL; SOSA, LDV; LATINI, A; GRONDONA, E; VENIER, AC

Mar del Plata

Congreso; REUNIÓN ANUAL DE LAS SOCIEDADES DE BIOCIENCIA; 2019

Socieda de Biociencia

The relationship between mitochondrial alterations and senescence as a regulatory process of cell growth in pituitary estrogen-induced tumors was recently described. Besides, it is known that energy deficiency and cellular damage with carcinogenic potential due to the accumulation of mutations in mitochondrial DNA are promoted by the estrogen oxidative action. In this context, we set out to evaluate possible 17β-estradiol (E2) pro-oxidant actions in vitro on mitochondrial dynamics and the damage response activation under pituitary tumor contexts.By subcutaneous implantation of capsules containing estradiol benzoate (30 mg) for 10 days, pituitary tumor development was induced in adult male Wistar rats (E10). Control group: implanted with empty capsules. Once the deadlines were met, the pituitary glands were extracted and their cells cultured and exposed to E2 (1-10-100nM) for 15, 30 and 60 min. The reactive oxygen species (ROS) generation was analyzed by flow cytometry, p-Nrf2 expression (response to oxidative damage) by immunofluorescence. Mitochondrial fusion and fision protein expression: MFN2 and OPA-1 and p-Drp1 by western blot.In tumoral cells, low doses of E2 (1nM) promoted a significant increase in the ROS generation after short exposure times, whereas, in normal cells, 10nM E2 induced this oxidative response after 30min of treatment. Likewise, an increase in p-Nrf2 expression was observed as the concentration and time of exposure to E2 increased. This same behavior was observed in the expression of the analyzed mitochondrial proteins, indicating a tendency towards fusion.The pro-oxidant environment that would promote E2 in tumor cells would be counterbalanced by the activation of antioxidant Nrf2 pathways. Oxidative stress would trigger alterations in mitochondrial dynamics, favoring the metabolic readaptation by fusion process. The cell viability would be guaranteed by these cellular responses meeting greater energy demands, typical of tumor contexts.