Pivotal role of NF-κB in cellular senescence of experimental pituitary tumours

MONGI-BRAGATO, BETHANIA; GRONDONA, EZEQUIEL; SOSA, LILIANA DEL VALLE; ZLOCOWSKI, NATACHA; VENIER, ANA CLARA; TORRES, ALICIA INÉS; LATINI, ALEXANDRA; LEAL, RODRIGO BAINY; GUTIÉRREZ, SILVINA; DE PAUL, ANA LUCÍA

JOURNAL OF ENDOCRINOLOGY

BIOSCIENTIFICA LTD

Año: 2020 vol. 245 p. 179 - 191

0022-0795

The molecular mechanisms underlying the capability of pituitary tumours to avoidunregulated cell proliferation are still not well understood. However, the NF-κBtranscription factor, which is able to modulate not only cellular senescence but alsotumour progression, has emerged as a targeted candidate. This work was focused onthe NF-κB role in cellular senescence during the progression of experimental pituitarytumours. Also, the contribution of the signalling pathways in senescence-associatedNF-κB activation and the senescence-associated secretory phenotype (SASP) and prosurvival-NF-κB target genes transcription were analysed. A robust NF-κB activation wasseen at E20?E40 of tumour development accompanied by a marked SA-β-Gal co-reactivityin the tumour pituitary parenchyma. The induction of TNFα and IL1-β as specific SASPrelated NF-κB target genes as well as Bcl-2 and Bcl-xl pro-survival genes was shown tobe accompanied by increases in the p-p38 MAPK protein levels, starting at the E20 stageand strengthening from 40 to 60 days of tumour growth. It is noteworthy that p-JNKdisplayed a similar pattern of activation during pituitary tumour development, whilep-AKT and p-ERK1/2 were downregulated. By employing a pharmacological strategy toabrogate NF-κB activity, we demonstrated a marked reduction in SA-β-Gal activity and aslight decrease in Ki67 immunopositive cells after NF-κB blockade. These results suggesta central role for NF-κB in the regulation of the cellular senescence programme, leadingto the strikingly benign intrinsic nature of pituitary adenomas.