Contribution of different signaling pathways on the development of estrogen-induced pituitary tumors: their role in senescence process

MONGI BRAGATO BETHANIA; EZEQUIEL GRONDONA; LILIANA DEL VALLE SOSA; LUCÍA CARREÑO; JUAN PETITI; SILVINA GUTIÉRREZ; ALICIA TORRES; ANA L DE PAUL

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

SAIC

Recently we demonstrated signs of cellular senescence as a growth control mechanism during the progression of experimental pituitary tumors. Also, it is known that Ras induces negative feedback response on PI3K/Akt and ERK1/2 pathways, thus promoting senescence. Oppositely, JNK and p38-stress signalling activation mediates key molecular events triggering the senescence program. Based on these evidences, we evaluated the contribution these signalling pathways on cellular senescence during the development of estrogen-induced pituitary tumors.To induce pituitary tumors, Wistar adult male rats were implanted with silastic capsules containing estradiol benzoate (30mg) for 10, 20, 40 and 60 days (E10-60). Control group was implanted with empty capsules. Subsequently, phosphorylated (p) and total ERK1/2; AKT; JNK and p38 protein levels were determined by Western blot. Also, pERK1/2, pAKT and senescent associated-b-Galactosidase (SA-b-gal) double staining was performed in cryosections from normal and tumoral pituitaries. Statistical analysis: ANOVA-Fischer test (p<0.05).An early pERK activation was detected at E10, followed by the suppression of this pathway, while pAKT expression was inhibited along tumoral progression. Concomitantly, pJNK and p38 progressively increased expression throughout the pituitary tumoral development. By analyzing the joint progression of senescence and proliferation biomarkers, we found discriminate differential areas in which pERK or pAKT positive cells were predominant and adjacent zones were a higher proportion of cells exhibited the SA-b-gal stain.These results suggest the existence of different regulatory mechanisms that attenuate the mitogenic signals during pituitary tumour development. Concomitantly, molecular events associated with cell senescence are trigged. This study delineates for first time the existence of an intricate signalling network during pituitary tumour development that may be involved in the control of tumoral growth.