Cobaltous chloride and hypoxia inhibit aryl hydrocarbon receptor-mediated responses in breast cancer cells
Cobaltous chloride and hypoxia inhibit aryl hydrocarbon receptor-mediated responses in breast cancer cells
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DOI：
10.1016/j.taap.2007.05.010
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发表时间：
2007-08-15
影响因子：
3.8
通讯作者：
Safe, Stephen
中科院分区：
文献类型：
--
作者：
Khan, Shaheen;Liu, Shengxi;Safe, Stephen
芳香烃受体（AhR）在雌激素受体（ER）阳性ZR-75乳腺癌细胞中表达。用2，3，7，8-四氯二苯并-p-二恶英（TCDD）处理诱导AhR-ER α I蛋白和mRNA水平，并且还激活与紫杉醇诱导的报告基因表达相关的抑制性AhR-ER α串扰。在ZR-75细胞生长在缺氧条件下，诱导这些AbR介导的反应TCDD显着抑制。这并不伴随着细胞核AhR水平降低或减少的AhR复合物与CYP 1A 1基因启动子的相互作用，在染色质免疫沉淀试验中确定。缺氧诱导的Ah-responsibility损失与缺氧诱导因子-1 α或其他螯合AhR核转位（AhR）蛋白的因子的诱导无关，缺氧条件下Arnt过表达不能恢复Ah-responsibility。抑制AhR介导的反式激活的NF kappa B的p65亚基不是由缺氧诱导的，并且在缺氧和常氧条件下生长的ZR-75细胞中主要存在于胞浆中。在ZR-75细胞在低氧条件下维持24小时，BRCA 1（乳腺癌细胞中AhR介导的反式激活的增强剂）显着减少，这有助于失去Ah-responsibility。在缺氧6小时的细胞中，BRCA I没有降低，但TCDD对BRCA I A I的诱导作用显著降低。TCDD与蛋白质合成抑制剂放线菌酮共处理ZR-75细胞6 h后，在缺氧和常氧条件下，ZR-75细胞中PAI-1的表达均增强。这些结果表明，缺氧迅速诱导抑制AH-反应性的蛋白质，这些蛋白质可能类似于组成型表达的AH-反应性抑制剂（常氧下），也被放线菌酮抑制。(c)2007年爱思唯尔公司All rights reserved.
The aryl hydrocarbon receptor (AhR) is expressed in estrogen receptor (ER)-positive ZR-75 breast cancer cells. Treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces CYP I A I protein and mRNA levels and also activates inhibitory AhR-ER alpha crosstalk associated with hormone-induced reporter gene expression. In ZR-75 cells grown under hypoxia, induction of these AbR-mediated responses by TCDD was significantly inhibited. This was not accompanied by decreased nuclear AhR levels or decreased interaction of the AhR complex with the CYP1A1 gene promoter as determined in a chromatin immunoprecipitation assay. Hypoxia-induced loss of Ah-responsiveness was not associated with induction of hypoxia-inducible factor-1 alpha or other factors that sequester the AhR nuclear translocation (Amt) protein, and overexpression of Arnt under hypoxia did not restore Ah-responsiveness. The p65 subunit of NF kappa B which inhibits AhR-mediated transactivation was not induced by hypoxia and was primarily cytosolic in ZR-75 cells grown under hypoxic and normoxic conditions. In ZR-75 cells maintained under hypoxic conditions for 24 h, BRCA 1 (an enhancer of AhR-mediated transactivation in breast cancer cells) was significantly decreased and this contributed to loss of Ah-responsiveness. In cells grown under hypoxia for 6 h, BRCA I was not decreased, but induction of CYP I A I by TCDD was significantly decreased. Cotreatment of ZR-75 cells with TCDD plus the protein synthesis inhibitor cycloheximide for 6 h enhanced CYP I A I expression in cells grown under hypoxia and normoxia. These results suggest that hypoxia rapidly induces protein(s) that inhibit Ah-responsiveness and these may be similar to constitutively expressed inhibitors of Ah-responsiveness (under normoxia) that are also inhibited by cycloheximide. (c) 2007 Elsevier Inc. All rights reserved.