Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity
Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity
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DOI：
10.1101/gad.17276711
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发表时间：
2011-10-15
影响因子：
10.5
通讯作者：
Lowe, Scott W.
中科院分区：
文献类型：
--
作者：
Chien, Yuchen;Scuoppo, Claudio;Lowe, Scott W.
细胞衰老是肿瘤发生的有效屏障，有助于某些化疗药物的抗肿瘤活性。衰老细胞经历由Rb和P53控制的稳定的细胞周期停滞，此外，还表现出衰老相关的分泌表型(SASP)，涉及产生加强衰老停滞、改变微环境和触发对衰老细胞的免疫监视的因子。通过对衰老染色质的蛋白质组学分析，我们确定核因子-kappa B亚基p65是积累在衰老细胞染色质上的主要转录因子。我们发现，核因子-kappa B作为SASP的主要调节因子，影响的基因表达比Rb和P53的总和还要多。在培养的成纤维细胞中，核因子-kappaB的抑制导致自然杀伤(NK)细胞逃避免疫识别，并与P53失活协同作用绕过衰老。在小鼠淋巴瘤模型中，抑制核因子-kappa B绕过了治疗诱导的衰老，产生了耐药性，早期复发，并降低了存活率。我们的结果表明，核因子-kappa B控制衰老程序的细胞自主和非细胞自主方面，并确定核因子-kappa B的肿瘤抑制功能，这有助于癌症治疗的结果。
Cellular senescence acts as a potent barrier to tumorigenesis and contributes to the anti-tumor activity of certain chemotherapeutic agents. Senescent cells undergo a stable cell cycle arrest controlled by RB and p53 and, in addition, display a senescence-associated secretory phenotype (SASP) involving the production of factors that reinforce the senescence arrest, alter the microenvironment, and trigger immune surveillance of the senescent cells. Through a proteomics analysis of senescent chromatin, we identified the nuclear factor-kappa B (NF-kappa B) subunit p65 as a major transcription factor that accumulates on chromatin of senescent cells. We found that NF-kappa B acts as a master regulator of the SASP, influencing the expression of more genes than RB and p53 combined. In cultured fibroblasts, NF-kappa B suppression causes escape from immune recognition by natural killer (NK) cells and cooperates with p53 inactivation to bypass senescence. In a mouse lymphoma model, NF-kappa B inhibition bypasses treatment-induced senescence, producing drug resistance, early relapse, and reduced survival. Our results demonstrate that NF-kappa B controls both cell-autonomous and non-cell-autonomous aspects of the senescence program and identify a tumor-suppressive function of NF-kappa B that contributes to the outcome of cancer therapy.