Role of CCL20 mediated immune cell recruitment in NF-κB mediated TRAIL resistance of pancreatic cancer
Role of CCL20 mediated immune cell recruitment in NF-κB mediated TRAIL resistance of pancreatic cancer
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DOI：
10.1016/j.bbamcr.2017.02.005
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发表时间：
2017-05-01
影响因子：
5.1
通讯作者：
Arlt, Alexander
中科院分区：
文献类型：
--
作者：
Geismann, Claudia;Grohmann, Frauke;Arlt, Alexander
胰腺导管腺癌（PDAC）是最致命的癌症之一。从临床观点来看，转录因子NF-κ B是特别重要的，因为该途径赋予细胞凋亡抗性并限制药物功效。然而，最丰富的NF-κ B亚基p65/RelA在治疗抗性中的作用是有据可查的，只有很少的知识的ReIA下游目标和它们的功能相关性在TRAIL介导的凋亡在PDAC是available.In目前的研究中，TRAIL抗性和敏感的PDAC细胞系进行了分析的差异表达的RelA靶基因，以确定RelA下游靶介导的TRAIL抗性。无偏全基因组表达分析表明，趋化因子CCL 20代表了抗性PDAC细胞中最强的TRAIL诱导的直接ReIA靶基因。出乎意料的是，通过siRNA、阻断抗体或通过下调唯一的CCL 20受体CCR 6靶向CCL 20对PDAC细胞死亡或癌细胞迁移没有影响，这与CCL 20在PDAC中的自分泌作用相反。然而，通过使用离体间接共培养系统，我们能够表明CCL 20作为旁分泌来募集免疫细胞。重要的是，CCL 20募集的免疫细胞进一步增加了产生CCL 20的PDAC细胞的TRAIL抗性。我们展示了治疗诱导的癌细胞与免疫细胞的串扰如何影响治疗反应，这是定制新型双特异性治疗所需的知识，这些治疗靶向肿瘤细胞以及免疫细胞。(C)2017爱思唯尔B. V.保留所有权利。
Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest cancers. From a clinical view, the transcription factor NF-kappa B is of particular importance, since this pathway confers apoptosis resistance and limits drug efficacy. Whereas the role of the most abundant NF-kappa B subunit p65/RelA in therapeutic resistance is well documented, only little knowledge of the ReIA downstream targets and their functional relevance in TRAIL mediated apoptosis in PDAC is available.In the present study TRAIL resistant and sensitive PDAC cell lines were analyzed for differentially expressed RelA target genes, to define RelA downstream targets mediating TRAIL resistance. The most upregulated target gene was then further functionally characterized.Unbiased genome-wide expression analysis demonstrated that the chemokine CCL20 represents the strongest TRAIL inducible direct ReIA target gene in resistant PDAC cells. Unexpectedly, targeting CCL20 by siRNA, blocking antibodies or by downregulation of the sole CCL20 receptor CCR6 had no effect on PDAC cell death or cancer cell migration, arguing against an autocrine role of CCL20 in PDAC. However, by using an ex vivo indirect co-culture system we were able to show that CCL20 acts paracrine to recruit immune cells. Importantly, CCL20-recruited immune cells further increase TRAIL resistance of CCL20-producing PDAC cells.In conclusion, our data show a functional role of a ReIA-CCL20 pathway in PDAC TRAIL resistance. We demonstrate how the therapy-induced cross-talk of cancer cells with immune cells affects treatment responses, knowledge needed to tailor novel bi-specific treatments, which target tumor cell as well as immune cells. (C) 2017 Elsevier B.V. All rights reserved.