Universidad Nacional de Córdoba, Facultad de Ciencias Médicas, Centro de Microscopía Electrónica, Córdoba, Argentina.
Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Investigaciones en Ciencias de la Salud (INICSA), Córdoba, Argentina.
J Endocrinol. 2020 May;245(2):179-191. doi: 10.1530/JOE-19-0506.
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.
尽管垂体肿瘤能够避免不受控制的细胞增殖的分子机制仍未得到很好的理解，但 NF-κB 转录因子已成为一个有针对性的候选因子，它能够调节细胞衰老，也能够调节肿瘤进展。这项工作集中研究了 NF-κB 在实验性垂体肿瘤进展过程中的细胞衰老中的作用。此外，还分析了信号通路在衰老相关 NF-κB 激活和衰老相关 secretory phenotype (SASP) 以及促生存-NF-κB 靶基因转录中的作用。在肿瘤发展的 E20-E40 期间观察到 NF-κB 的强烈激活，伴随着肿瘤垂体实质中明显的 SA-β-Gal 共反应性。诱导 TNFα 和 IL1-β 作为特定的 SASP 相关 NF-κB 靶基因，以及 Bcl-2 和 Bcl-xl 促生存基因的转录显示，p-p38 MAPK 蛋白水平的增加伴随着 p38 MAPK 的增加，从 E20 阶段开始，并从肿瘤生长的 40 天到 60 天增强。值得注意的是，p-JNK 在垂体肿瘤发育过程中表现出类似的激活模式，而 p-AKT 和 p-ERK1/2 则下调。通过采用药理学策略来阻断 NF-κB 活性，我们在 NF-κB 阻断后观察到 SA-β-Gal 活性显著降低，Ki67 免疫阳性细胞略有减少。这些结果表明 NF-κB 在调节细胞衰老程序中起着核心作用，导致垂体腺瘤具有明显的良性内在性质。
