Chen A, Xu J, Johnson A C
Department of Pathology, Louisiana State University Health Sciences Center in Shreveport, LA 71130, USA.
Oncogene. 2006 Jan 12;25(2):278-87. doi: 10.1038/sj.onc.1209019.
High expression of epidermal growth factor receptor (EGFR) is found in a variety of solid tumors, including colorectal cancer. EGFR has been identified as a rational target for anticancer therapy. Curcumin, the yellow pigment of turmeric in curry, has received attention as a promising dietary supplement for cancer prevention and treatment. We recently reported that curcumin inhibited the growth of human colon cancer-derived Moser cells by suppressing gene expression of cyclinD1 and EGFR. The aim of the present study was to explore the molecular mechanisms underlying curcumin inhibition of gene expression of EGFR in colon cancer cells. The generality of the inhibitory effect of curcumin on gene expression of EGFR was verified in other human colon cancer-derived cell lines, including Caco-2 and HT-29 cells. Promoter deletion assays and site-directed mutageneses identified a binding site for the transcription factor early growth response-1 (Egr-1) in egfr promoter as a putative curcumin response element in regulating the promoter activity of the gene in Moser cells. Electrophoretic mobility shift assays demonstrated that curcumin significantly reduced the DNA-binding activity of the transcription factor Egr-1 to the curcumin response element. In addition, curcumin reduced the trans-activation activity of Egr-1 by suppressing egr-1 gene expression, which required interruption of the ERK signal pathway and reduction of the level of phosphorylation of Elk-1 and its activity. Taken together, our results demonstrated that curcumin inhibited human colon cancer cell growth by suppressing gene expression of EGFR through reducing the trans-activation activity of Egr-1. These results provided novel insights into the mechanisms of curcumin inhibition of colon cancer cell growth and potential therapeutic strategies for treatment of colon cancer.
在包括结直肠癌在内的多种实体瘤中都发现了表皮生长因子受体（EGFR）的高表达。EGFR已被确定为抗癌治疗的合理靶点。姜黄素是咖喱中姜黄的黄色色素，作为一种有前景的癌症预防和治疗膳食补充剂受到了关注。我们最近报道，姜黄素通过抑制细胞周期蛋白D1和EGFR的基因表达来抑制人结肠癌来源的莫泽细胞的生长。本研究的目的是探讨姜黄素抑制结肠癌细胞中EGFR基因表达的分子机制。在其他来源于人结肠癌的细胞系，包括Caco-2和HT-29细胞中，验证了姜黄素对EGFR基因表达抑制作用的普遍性。启动子缺失分析和定点诱变确定了egfr启动子中转录因子早期生长反应-1（Egr-1）的结合位点，作为调节莫泽细胞中该基因启动子活性的假定姜黄素反应元件。电泳迁移率变动分析表明，姜黄素显著降低了转录因子Egr-1与姜黄素反应元件的DNA结合活性。此外，姜黄素通过抑制egr-1基因表达降低了Egr-1的反式激活活性，这需要中断ERK信号通路并降低Elk-1的磷酸化水平及其活性。综上所述，我们的结果表明，姜黄素通过降低Egr-1的反式激活活性来抑制EGFR基因表达，从而抑制人结肠癌细胞的生长。这些结果为姜黄素抑制结肠癌细胞生长的机制和结肠癌治疗的潜在策略提供了新的见解。
