IDO1 and IDO2 are expressed in human tumors: levo- but not dextro-1-methyl tryptophan inhibits tryptophan catabolism
IDO1 and IDO2 are expressed in human tumors: levo- but not dextro-1-methyl tryptophan inhibits tryptophan catabolism
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DOI：
10.1007/s00262-008-0513-6
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发表时间：
2009-01-01
影响因子：
5.8
通讯作者：
Terness, Peter
中科院分区：
文献类型：
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作者：
Loeb, Stefan;Koenigsrainer, Alfred;Terness, Peter
目的 吲哚胺-2,3-双加氧酶 (IDO) 是一种可在多种细胞中诱导的免疫抑制分子。除了经典的 IDO (IDO1) 之外，最近还描述了一种新的变体 IDO2。当在树突状细胞 (DC) 或癌细胞中表达时，IDO 被认为可以抑制对肿瘤的免疫反应。一种新的癌症治疗方法设想用 1-甲基-色氨酸 (1MT) 抑制 IDO。左旋异构体 (L-1MT) 阻断 IDO1，而临床试验中使用的右旋异构体 (D-1MT) 则抑制 IDO2。在这里，我们分析了人类癌细胞中的 IDO2 表达以及两种 1-MT 亚型对 IDO 活性的影响。方法通过 RT-PCR 检测手术切除的人类原发性肿瘤以及人类癌细胞系的 IDO1 和 IDO2 表达。通过用 IDO1-speciWc siRNA 转染来阻断 Hela 细胞的 IDO1 活性，并通过 RP-HPLC 分析色氨酸降解。研究了D-1MT和L-1MT对Hela细胞和人结肠癌分离蛋白IDO活性的影响。结果人原发性胃癌、结肠癌和肾细胞癌持续表达IDO1和IDO2 mRNA，而癌细胞系必须由干扰素-γ(IFN-γ)诱导。用IDO1特异性siRNA处理Hela细胞导致色氨酸降解完全消除。只有 L-1MT（而非 D-1MT）能够阻断 IFN-γ 处理的 Hela 细胞以及原发性人类结肠癌的蛋白质分离物中的 IDO 活性。结论 尽管IDO2在人类肿瘤中表达，但色氨酸降解完全由IDO1提供。重要的是，D-1MT 不会抑制恶性细胞的 IDO 活性。如果正在进行的临床研究显示 D-1MT 具有治疗作用，这不能归因于肿瘤细胞中 IDO 的抑制。
Objectives Indoleamine-2,3- Dioxygenase (IDO) is an immunosuppressive molecule inducible in various cells. In addition to classic IDO (IDO1), a new variant, IDO2, has recently been described. When expressed in dendritic cells (DCs) or cancer cells, IDO was thought to suppress the immune response to tumors. A novel therapeutic approach in cancer envisages inhibition of IDO with 1-methyl-tryptophan (1MT). The levo-isoform (L-1MT) blocks IDO1, whereas dextro-1MT (D-1MT), which is used in clinical trials, inhibits IDO2. Here we analyze IDO2 expression in human cancer cells and the impact of both 1-MT isoforms on IDO activity. Methods Surgically extirpated human primary tumors as well as human cancer cell lines were tested for IDO1 and IDO2 expression by RT-PCR. IDO1 activity of Hela cells was blocked by transfection with IDO1-speciWc siRNA and analysed for tryptophan degradation by RP-HPLC. The impact of D-1MT and L-1MT on IDO activity of Hela cells and protein isolates of human colon cancer were studied. Results Human primary gastric, colon and renal cell carcinomas constitutively expressed both, IDO1 and IDO2 mRNA, whereas cancer cells lines had to be induced to by Interferon-gamma (IFN-gamma). Treatment of Hela cells with IDO1-speciWc siRNA resulted in complete abrogation of tryptophan degradation. Only L-1MT, and not D-1MT, was able to block IDO activity in IFN-gamma-treated Hela cells as well as in protein isolates of primary human colon cancer. Conclusions Although IDO2 is expressed in human tumors, tryptophan degradation is entirely provided by IDO1. Importantly, D-1MT does not inhibit the IDO activity of malignant cells. If ongoing clinical studies show a therapeutic effect of D-1MT, this cannot be attributed to inhibition of IDO in tumor cells.