NF-κB-dependent cytokine secretion controls Fas expression on chemotherapy-induced premature senescent tumor cells
NF-κB-dependent cytokine secretion controls Fas expression on chemotherapy-induced premature senescent tumor cells
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DOI：
10.1038/onc.2011.1
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发表时间：
2011-06-01
期刊：
影响因子：
8
通讯作者：
Leonardi, A.
中科院分区：
文献类型：
--
作者：
Crescenzi, E.;Pacifico, F.;Leonardi, A.
肿瘤细胞中衰老表型的诱导与抗癌免疫应答有关，然而，介导这些现象的分子机制尚未确定。在这项研究中，我们提出的证据表明，诱导人类癌细胞系的早衰诱导Fas表达，并失去抵抗Fas诱导的凋亡。通过使用激动性抗体CH 11或重组配体APO 010触发Fas激活负责细胞死亡的凋亡途径。衰老细胞分泌促炎细胞因子，特别是TNF-α和IFN-γ，介导Fas上调。事实上，用TNF-α和IFN-γ处理增殖的癌细胞系上调Fas表达，而通过使用中和抗体阻断TNF-α和IFN-γ降低衰老细胞中的Fas表达。我们还证明了NF-κ B在控制早衰细胞的衰老相关分泌表型（SASP）中具有核心作用，并且NF-κ B转录控制的TNF-α和IFN-γ是Fas上调的主要介质。我们的数据表明，存在一个NF-κ B B依赖性自分泌环，由TNF-α和IFN-γ介导，负责Fas在衰老细胞表面的表达，并杀死它们。Oncogene（2011）30，2707-2717; doi：10.1038/onc.2011.1; 2011年1月31日在线发表
Induction of a senescent phenotype in tumor cells has been linked to anticancer immune response, however, the molecular mechanisms mediating these phenomenon have not yet been determined. In this study, we present evidence that induction of premature senescence in human cancer cell lines induces Fas expression, and loss of resistance to Fas-induced apoptosis. Triggering of Fas by using the agonistic antibody CH11 or the recombinant ligand APO010, activates an apoptotic pathway responsible for cell death. Secretion of pro-inflammatory cytokines by the senescent cells, particularly TNF-alpha and IFN-gamma, mediates Fas upregulation. Indeed, treatment of proliferating cancer cell lines with TNF-alpha and IFN-gamma, upregulates Fas expression, while blocking TNF-alpha and IFN-gamma by using neutralizing antibodies, decreases Fas expression in senescent cells. We also demonstrate that NF-kappa B has a central role in controlling the senescence-associated secretory phenotype (SASP) by the premature senescent cells, and that TNF-alpha and IFN-gamma, transcriptionally controlled by NF-kappa B, are the main mediators of Fas upregulation. Our data suggest the existence of an NF-kappa B- dependent autocrine loop, mediated by TNF-alpha and IFN-gamma, responsible for expression of Fas on the surface of senescent cells, and for their killing. Oncogene (2011) 30, 2707-2717; doi: 10.1038/onc.2011.1; published online 31 January 2011