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

The molecular mechanisms underlying the capability of pituitary tumours to avoid unregulated cell proliferation are still not well understood. However, the NF-kappa B transcription factor, which is able to modulate not only cellular senescence but also tumour progression, has emerged as a targeted candidate. This work was focused on the NF-kappa B role in cellular senescence during the progression of experimental pituitary tumours. Also, the contribution of the signalling pathways in senescence-associated NF-kappa B activation and the senescence-associated secretory phenotype (SASP) and prosurvival-NF-kappa B target genes transcription were analysed. A robust NF-kappa B activation was seen at E20-E40 of tumour development accompanied by a marked SA-beta-Gal co-reactivity in the tumour pituitary parenchyma. The induction of TNF alpha and IL1-beta as specific SASP-related NF-kappa B target genes as well as Bcl-2 and Bcl-xl pro-survival genes was shown to be accompanied by increases in the p-p38 MAPK protein levels, starting at the E20 stage and strengthening from 40 to 60 days of tumour growth. It is noteworthy that p-JNK displayed a similar pattern of activation during pituitary tumour development, while p-AKT and p-ERK1/2 were downregulated. By employing a pharmacological strategy to abrogate NF-kappa B activity, we demonstrated a marked reduction in SA-beta-Gal activity and a slight decrease in Ki67 immunopositive cells after NF-kappa B blockade. These results suggest a central role for NF-kappa B in the regulation of the cellular senescence programme, leading to the strikingly benign intrinsic nature of pituitary adenomas.