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

Abstract

The molecular mechanisms underlying the capability of pituitary tumours to avoid unregulated cell proliferation are still not well understood. However, the NF-κB 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-κB role in cellular senescence during the progression of experimental pituitary tumours. Also, the contribution of the signalling pathways in senescence-associated NF-κB activation and the senescence-associated secretory phenotype (SASP) and pro-survival-NF-κB target genes transcription were analysed. A robust NF-κB activation was seen at E20–E40 of tumour development accompanied by a marked SA-β-Gal co-reactivity in the tumour pituitary parenchyma. The induction of TNFα and IL1-β as specific SASP-related NF-κB 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-κB activity, we demonstrated a marked reduction in SA-β-Gal activity and a slight decrease in Ki67 immunopositive cells after NF-κB blockade. These results suggest a central role for NF-κB in the regulation of the cellular senescence programme, leading to the strikingly benign intrinsic nature of pituitary adenomas.

Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer

“…2j ). RelA/p65 , a subunit of NF-kB and a key regulator of the SASP 27 , 28 , was the most upregulated gene of the NF-kB pathway, whereas Cxcl1 , Il6 , Il1a and Cxcl15 were the most enriched SASP genes, in line with previous data from our and different research teams 5 , 27 , 28 (Fig. 1l–o ).…”

“…Pathway analysis showed that JAK-STAT, NF-kB, p53, MAPK and TNFα signaling, known to be upregulated in senescent tumor cells, were mostly activated in the Sene_1–5 clusters. Instead, Sene_0 and Sene_6 clusters were characterized by the upregulation of WNT and PI3K patways 27 , 36 – 42 (Fig. 2f ).…”

Biomarkers of aging

“…Emerging evidence indicates that the SASP can reinforce the senescence arrest and mediate cross-talk between senescent cells and immune cells within their microenvironment (Acosta et al, 2008;Krizhanovsky et al, 2008;Krtolica et al, 2001;Kuilman et al, 2008). NF-κB activation has been proposed as a master regulator in senescence that is required for SASP production and contributes to cell cycle arrest (Chien et al, 2011;Mongi-Bragato et al, 2020;Salminen et al, 2012b). NF-κB transcription factors contain both the Rel family proteins (RelA/p65, c-Rel and RelB) and NF-κB components (p50/ p105 and p52/p100), which are dimerized with each other in the cytoplasm and inhibited by binding to IκB proteins (Hoffmann and Baltimore, 2006).…”

Oxidative stress in pituitary neuroendocrine tumors: Affecting the tumor microenvironment and becoming a new target for pituitary neuroendocrine tumor therapy

“…VEGF and matrix metalloproteinase 9, as paracrine components of SASP, may contribute to the metastasis of PitNETs. [76][77][78][79][80] Upregulation of VEGF usually implies tumor development and malignant transformation, and this is indeed the case in PitNETs. 15,81 Compared with adjacent normal pituitary tissue, PitNET tissue shows decreased VEGF expression, while pituitary carcinoma tissues show increased expression.…”