A New Cyclooxygenase-2 Inhibitor, (1E,4E)-1,5-Bis(2-bromophenyl)penta-1,4-dien-3-one (GL63) Suppresses Cyclooxygenase-2 Gene Expression in Human Lung Epithelial Cancer Cells: Coupled mRNA Stabilization and Posttranscriptional Inhibition
A New Cyclooxygenase-2 Inhibitor, (1E,4E)-1,5-Bis(2-bromophenyl)penta-1,4-dien-3-one (GL63) Suppresses Cyclooxygenase-2 Gene Expression in Human Lung Epithelial Cancer Cells: Coupled mRNA Stabilization and Posttranscriptional Inhibition
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一种新型 Cyclooxygenase-2 抑制剂 (1E,4E)-1,5-Bis(2-bromoryl)penta-1,4-dien-3-one (GL63) 可抑制人肺上皮癌细胞中的 Cyclooxygenase-2 基因表达：
DOI：
10.1248/bpb.33.1170
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发表时间：
2010-07-01
影响因子：
2
通讯作者：
Yang, Huiling
中科院分区：
文献类型：
--
作者：
Xiao, Jian;Tan, Yi;Yang, Huiling
肺癌是世界范围内发病率和死亡率的主要原因。环氧化酶-2（考克斯-2）在肺癌中表达上调，被认为是一个有吸引力的治疗靶点。本研究探讨了姜黄素及其类似物对佛波醇12-肉豆蔻酸酯13-乙酸酯（PMA）诱导的考克斯-2表达的影响。我们发现，一种新的姜黄素类似物（GL 63）抑制PMA诱导的考克斯-2 mRNA和蛋白水平在H460细胞中的程度比姜黄素。为了理解控制考克斯-2调节的分子机制，检查了对考克斯-2 mRNA降解的影响;我们发现，GL 63通过减少人抗原R（HuR）的细胞质定位和蛋白丰度来显著降低考克斯-2 mRNA稳定性。3 '-非翻译区（3'-UTR）报告基因分析也显示GL 63显著降低了3 '-UTR绿色荧光蛋白值，表明对考克斯-2 mRNA的去稳定作用可能与考克斯-2的转录后抑制相关联。综上所述，我们的研究结果提供了证据表明，新的姜黄素类似物可以有效地抑制PMA诱导的H460细胞中的考克斯-2表达，这是一种与考克斯-2 mRNA稳定性和转录后调控相关的机制。
Lung cancer is a leading cause of morbidity and mortality worldwide. Cyclooxygenase-2 (COX-2) expression is upregulated in lung carcinomas and is considered an attractive therapeutic target. In this study, the effect of curcumin and curcumin analogues on COX-2 expression induced by phorbol 12-myristate 13-acetate (PMA) were investigated. We found that a novel curcumin analogue (GL63) inhibited PMA-induced COX-2 mRNA and protein levels in H460 cells to a greater degree than curcumin. To understand the molecular mechanisms governing COX-2 regulation, the effect on COX-2 mRNA degradation was examined; we found that GL63 significantly decreased COX-2 mRNA stability by reducing cytoplasmic localization and protein abundance of human antigen R (HuR). The 3'-untranslated region (3'-UTR) report gene assay also showed GL63 substantially reduced the 3'-UTR green fluorescent protein values, indicating that the destabilizing effect on COX-2 mRNA may be couple with the posttranscriptional inhibition of COX-2. Taken together, our results provide evidence that the novel curcumin analogue can effectively inhibit PMA-induced COX-2 expression in H460 cells, a mechanism associated with COX-2 mRNA stability and post-transcriptional regulation.