Interaction between the nuclear factor kappa B (NF-KB) and the estrogen receptor alpha (ERA) in the cellular senescence process during the development of estrogen induced pituitary tumors

MONGI-BRAGATO B. ; GRONDONA E.; SOSA L.; CARREÑO L. ; PETITI J.P.; GUTIÉRREZ S.; TORRES A.I.; DE PAUL A.L.

Mar del Plata

Congreso; LXI Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2016

Evidences from our group demonstrated the emergence of cellular senescence process as a growth control mechanism during the progression of estrogen-induced pituitary tumors. Also, estrogen exerts a modulatory action on pituitary cells proliferation. Considering the preponderant role of NF-kB (p65) in cellular senescence and points of convergence between ERa and NF-kB signaling pathways in cell cycle control, we evaluate the contribution of the interaction between these two proteins in the pituitary senescence in experimental pituitary tumors. Wistar adult male rats were implanted subcutaneously with silastic capsules containing estradiol benzoate (30mg) for 10, 20, 40 and 60 days (E10-60). The control group was implanted with empty capsules. Subsequently, ERa:NF-kB immunoprecipitation was performed at the different stages of tumoral development. NF-kB and IkBa levels were also determined from nuclear and cytosolic fractions by Western blot. The ERa:NF-kB co-localization was analyzed by immunofluorescence (IF) and transmission electron microscopy (TEM). Statistical analysis: ANOVA-Fischer test (p<0.05). During the course of estrogen-induced pituitary tumoral development, a significant ERa:NF-kB association was detected, with a marked interaction at E10 and E60, result that was corroborated by IF and TEM. Also, a significant increase in NF-kB and IkBa protein levels in the cytosolic compartment was detected. Interestingly, a substantial increased in the NF-kB nuclear levels was evidenced at E20 and E40 compared to those observed at E10 and E60. Probably, ERa recruits NF-kB at the cytoplasmic compartment in order to inhibit their function as a transcription factor and thereby modulate cell senescence-associated molecular mechanisms during the progression of the experimental pituitary tumor. These results suggest a cross-talk between NF-kB and ERa signaling pathway that may lead to the emergence of cellular senescence, thus contributing to the control of the cell growth.