(-)-Epigallocatechin gallate inhibits the expression of indoleamine 2,3-dioxygenase in human colorectal cancer cells.
(-)-Epigallocatechin gallate inhibits the expression of indoleamine 2,3-dioxygenase in human colorectal cancer cells.
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DOI：
10.3892/ol.2012.761
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发表时间：
2012-09
期刊：
影响因子：
2.9
通讯作者：
Kengo Ogawa;T. Hara;M. Shimizu;J. Nagano;T. Ohno;Masato Hoshi;Hiroyasu Ito;H. Tsurumi;Kuniaki Saito;M. Seishima;H. Moriwaki
中科院分区：
文献类型：
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作者：
Kengo Ogawa;T. Hara;M. Shimizu;J. Nagano;T. Ohno;Masato Hoshi;Hiroyasu Ito;H. Tsurumi;Kuniaki Saito;M. Seishima;H. Moriwaki
免疫逃逸是肿瘤细胞避免肿瘤特异性免疫应答的能力，发生在几种类型的人类恶性肿瘤（包括结直肠癌（CRC））的发展和进展期间。吲哚胺2，3-双加氧酶（IDO）是色氨酸分解代谢酶，在调节免疫反应中起重要作用，并为肿瘤细胞提供了逃避免疫系统的有效工具。在本研究中，我们研究了绿色茶中的主要儿茶素（-）-表没食子儿茶素没食子酸酯（EGCG）对干扰素（IFN）-γ诱导的人CRC细胞IDO表达的抑制作用。我们发现IFN-γ增加了HT 29和SW 837 CRC细胞系中IDO蛋白和mRNA的表达水平。用EGCG处理SW 837细胞后，IFN-γ诱导的IDO蛋白和mRNA的表达呈剂量依赖性降低。通过培养基中L-犬尿氨酸的浓度确定的IDO的酶活性也被EGCG处理显著抑制。EGCG能显著抑制IFN-γ诱导的STAT 1磷酸化。报告基因分析表明，EGCG抑制了由STAT 1磷酸化激活的IDO启动子、IFN刺激的应答元件和IFN-γ激活序列的转录活性。这些结果表明，EGCG可能发挥抗肿瘤作用的CRC，至少部分，通过抑制STAT 1激活抑制IDO的表达和功能。因此，EGCG可以作为一种潜在的抗肿瘤免疫治疗剂，并可用于CRC的化学预防和/或治疗。
Immune escape, the ability of tumor cells to avoid tumor-specific immune responses, occurs during the development and progression of several types of human malignancies, including colorectal cancer (CRC). Indoleamine 2,3-dioxygenase (IDO), the tryptophan catabolic enzyme, plays a significant role in regulating the immune response and provides tumor cells with a potent tool to evade the immune system. In the present study, we examined the effects of (-)-epigallocatechin gallate (EGCG), the major catechin in green tea, on the inhibition of IDO expression induced by interferon (IFN)-γ in human CRC cells. We found that IFN-γ increased the expression levels of IDO protein and mRNA in HT29 and SW837 CRC cell lines. Treatment of SW837 cells with EGCG significantly decreased IFN-γ-induced expression of IDO protein and mRNA in a dose-dependent manner. Enzymatic activity of IDO, determined by the concentration of L-kynurenine in the culture medium, was also significantly inhibited by EGCG treatment. Phosphorylation of signal transducer and activator of transcription 1 (STAT1) induced by IFN-γ was also significantly inhibited by EGCG. Reporter assays indicated that EGCG inhibited the transcriptional activities of IDO promoters, IFN-stimulated response element and IFN-γ activation sequence, activated by STAT1 phosphorylation. These findings suggest that EGCG may exert antitumor effects on CRC, at least in part, by inhibiting the expression and function of IDO through the suppression of STAT1 activation. EGCG may, thus, serve as a potential agent for antitumor immunotherapy and be useful in the chemoprevention and/or treatment of CRC.