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首页> 外文期刊>Glia >Suppression of TDO-Mediated Tryptophan Catabolism in Glioblastoma Cells by a Steroid-Responsive FKBP52-Dependent Pathway
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Suppression of TDO-Mediated Tryptophan Catabolism in Glioblastoma Cells by a Steroid-Responsive FKBP52-Dependent Pathway

机译：通过类固醇响应性FKBP52依赖性途径抑制胶质母细胞瘤细胞中TDO介导的色氨酸分解代谢。

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摘要

Tryptophan catabolism is increasingly recognized as a key and druggable molecular mechanism active in cancer, immune, and glioneural cells and involved in the modulation of antitumor immunity, autoimmunity and glioneural function. In addition to the pivotal rate limiting enzyme indoleamine-2,3-dioxygenase, expression of tryptophan-2,3-dioxygenase (TDO) has recently been described as an alternative pathway responsible for constitutive tryptophan degradation in malignant gliomas and other types of cancer. In addition, TDO has been implicated as a key regulator of neurotoxicity involved in neurodegenerative diseases and ageing. The pathways regulating TDO expression, however, are largely unknown. Here, a siRNA-based transcription factor profiling in human glioblastoma cells revealed that the expression of human TDO is suppressed by endogenous glucocorticoid signaling. Similarly, treatment of glioblastoma cells with the synthetic glucocorticoid dexamethasone led to a reduction of TDO expression and activity in vitro and in vivo. TDO inhibition was dependent on the immunophilin FKBP52, whose FK1 domain physically interacted with the glucocorticoid receptor as demonstrated by bimolecular fluorescence complementation and in situ proximity ligation assays. Accordingly, gene expression profile analyses revealed negative correlation of FKBP52 and TDO in glial and neural tumors and in normal brain. Knockdown of FKBP52 and treatment with the FK-binding immunosuppressant FK506 enhanced TDO expression and activity in glioblastoma cells. In summary, we identify a novel steroid-responsive FKBP52-dependent pathway suppressing the expression and activity of TDO, a central and rate-limiting enzyme in tryptophan metabolism, in human gliomas. GLIA 2015;63:78-90
机译：色氨酸分解代谢日益被认为是在癌症，免疫和神经胶质细胞中活跃的关键且可药物化的分子机制，并参与抗肿瘤免疫，自身免疫和神经胶质功能的调节。除了关键的速率限制酶吲哚胺-2,3-双加氧酶外，色氨酸-2,3-双加氧酶（TDO）的表达最近已被描述为导致恶性神经胶质瘤和其他类型癌症中组成性色氨酸降解的另一种途径。另外，TDO被认为是涉及神经退行性疾病和衰老的神经毒性的关键调节剂。然而，调节TDO表达的途径在很大程度上是未知的。在此，人胶质母细胞瘤细胞中基于siRNA的转录因子分析揭示了人TDO的表达被内源性糖皮质激素信号传导抑制。类似地，用合成的糖皮质激素地塞米松治疗胶质母细胞瘤细胞导致体外和体内TDO表达和活性降低。 TDO抑制依赖于亲免蛋白FKBP52，其FK1结构域与糖皮质激素受体发生物理相互作用，如双分子荧光互补法和原位邻近连接测定所证实。因此，基因表达谱分析揭示了FKBP52和TDO在神经胶质和神经肿瘤以及正常脑中呈负相关。击倒FKBP52并用FK结合免疫抑制剂FK506处理可增强胶质母细胞瘤细胞的TDO表达和活性。总而言之，我们确定了一种新型的类固醇响应性FKBP52依赖性途径，可抑制人神经胶质瘤中TDO（色氨酸代谢中的中枢和限速酶）的表达和活性。 GLIA 2015; 63：78-90

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