Ah receptor antagonism inhibits constitutive and cytokine inducible IL6 production in head and neck tumor cell lines.
Ah receptor antagonism inhibits constitutive and cytokine inducible IL6 production in head and neck tumor cell lines.
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DOI：
10.1002/mc.20702
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发表时间：
2011-03
影响因子：
4.6
通讯作者：
Perdew, Gary H.
中科院分区：
文献类型：
--
作者：
DiNatale, Brett C.;Schroeder, Jennifer C.;Perdew, Gary H.
越来越多的证据表明芳烃受体（AHR）通过多种机制在肿瘤进展中发挥作用。我们之前已经证明，在某些通常对细胞因子介导的 IL6 诱导无反应的癌细胞系中，用激动剂 2,3,7,8-四氯二苯并-对二恶英激活 AHR 会去抑制 IL6 启动子，并允许在 IL1β 治疗后进行协同诱导。发生这种情况的机制涉及配体 AHR 从转录起始位点上游结合并解除含有 HDAC 的辅阻遏物复合物，从而产生更适合 NF-κB 激活的启动子结构。这一事实，结合对激活 AHR 的多种内源性化学物质的观察，促使我们研究其在高细胞因子产生癌细胞系基础表达中的作用。目前的研究提供的证据表明，几种头颈鳞状细胞癌细胞系在 IL6 启动子处具有一定水平的组成型结合 AHR，从而允许更高的基础且易于诱导的 IL6 转录。用 AHR 拮抗剂处理这些细胞系导致 AHR 从 IL6 启动子上消失并募集辅阻遏物复合物，从而减少细胞因子的表达。头颈鳞状细胞癌通常是一种高细胞因子产生的肿瘤类型，IL6 表达水平与疾病侵袭性相关。因此，AHR 拮抗剂治疗可以代表一种新型的患者辅助疗法，降低促生长和抗凋亡信号传导，同时将全身副作用降至最低。
There is increasing evidence that the aryl hydrocarbon receptor (AHR) plays a role in tumor progression through numerous mechanisms. We have previously shown that, in certain cancer cell lines that are typically non-responsive to cytokine-mediated IL6 induction, activation of the AHR with the agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin derepresses the IL6 promoter and allows for synergistic induction following IL1β treatment. The mechanism by which this occurs involves liganded AHR binding upstream from the transcription start site and dismissing HDAC-containing corepressor complexes, giving rise to a promoter structure that is more amenable to NF-κB activation. This fact, combined with observations of multiple endogenously-produced chemicals activating the AHR, led us to study its role in basal expression among high cytokine-producing cancer cell lines. The current study provides evidence that several head and neck squamous cell carcinoma cell lines have a level of constitutively bound AHR at the IL6 promoter, allowing for higher basal and readily inducible IL6 transcription. Treatment of these cell lines with an AHR antagonist led to dismissal of the AHR from the IL6 promoter and recruitment of corepressor complexes, thus diminishing cytokine expression. Head and neck squamous cell carcinoma is typically a high cytokine-producing tumor type, with IL6 expression levels correlating with disease aggressiveness. For this reason, AHR antagonist treatment could represent a novel adjuvant therapy for patients, lowering pro-growth and anti-apoptotic signaling with minimal systemic side effects.
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