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IDO1 和 TDO 通过 Kyn-AhR-AQP4 信号通路促进神经胶质瘤的恶性进展。

Both IDO1 and TDO contribute to the malignancy of gliomas via the Kyn-AhR-AQP4 signaling pathway.

机构信息

State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Songhu Road 2005, Shanghai, 200438, China.

Department of Neurosurgery, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Kongjiang Road 1665, Shanghai, 200092, China.

出版信息

Signal Transduct Target Ther. 2020 Feb 21;5(1):10. doi: 10.1038/s41392-019-0103-4.

DOI:10.1038/s41392-019-0103-4
PMID:32296044
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7033114/
Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1), indoleamine 2,3-dioxygenase 2 (IDO2), and tryptophan 2,3-dioxygenase (TDO) initiate the first step of the kynurenine pathway (KP), leading to the transformation of L-tryptophan (Trp) into L-kynurenine (Kyn) and other downstream metabolites. Kyn is known as an endogenous ligand of the aryl hydrocarbon receptor (AhR). Activation of AhR through TDO-derived Kyn is a novel mechanism to support tumor growth in gliomas. However, the role of IDO1 and IDO2 in this mechanism is still unknown. Herein, by using clinical samples, we found that the expression and activity of IDO1 and/or TDO (IDO1/TDO) rather than IDO2 were positively correlated with the pathologic grades of gliomas. The expression of IDO1/TDO rather than IDO2 was positively correlated with the Ki67 index and overall survival. The expression of IDO1/TDO was positively correlated with the expression of aquaporin 4 (AQP4), implying the potential involvement of IDO1/TDO in glioma cell motility. Mechanistically, we found that IDO1/TDO accounted for the release of Kyn, which activated AhR to promote cell motility via the Kyn-AhR-AQP4 signaling pathway in U87MG glioma cells. RY103, an IDO1/TDO dual inhibitor, could block the IDO1/TDO-Kyn-AhR-AQP4 signaling pathway and exert anti-glioma effects in GL261 orthotopic glioma mice. Together, our results showed that the IDO1/TDO-Kyn-AhR-AQP4 signaling pathway is a new mechanism underlying the malignancy of gliomas, and suggest that both IDO1 and TDO might be valuable therapeutic targets for gliomas.

摘要

色氨酸 2,3-双加氧酶 1（IDO1）、色氨酸 2,3-双加氧酶 2（IDO2）和色氨酸 2,3-双加氧酶（TDO）启动犬尿氨酸途径（KP）的第一步，导致 L-色氨酸（Trp）转化为 L-犬尿氨酸（Kyn）和其他下游代谢物。Kyn 被认为是芳烃受体（AhR）的内源性配体。通过 TDO 衍生的 Kyn 激活 AhR 是支持神经胶质瘤中肿瘤生长的新机制。然而，IDO1 和 IDO2 在该机制中的作用尚不清楚。在此，我们通过使用临床样本发现，IDO1/TDO（IDO1 和 TDO 的表达和活性）而不是 IDO2 的表达和活性与神经胶质瘤的病理分级呈正相关。IDO1/TDO 的表达与 Ki67 指数和总生存期呈正相关。IDO1/TDO 的表达与水通道蛋白 4（AQP4）的表达呈正相关，表明 IDO1/TDO 可能参与神经胶质瘤细胞的运动。从机制上讲，我们发现 IDO1/TDO 负责犬尿氨酸的释放，该犬尿氨酸激活 AhR 通过 Kyn-AhR-AQP4 信号通路促进 U87MG 神经胶质瘤细胞的运动。IDO1/TDO 双重抑制剂 RY103 可阻断 IDO1/TDO-Kyn-AhR-AQP4 信号通路，并在 GL261 原位神经胶质瘤小鼠中发挥抗神经胶质瘤作用。总之，我们的研究结果表明 IDO1/TDO-Kyn-AhR-AQP4 信号通路是神经胶质瘤恶性程度的新机制，并提示 IDO1 和 TDO 可能是神经胶质瘤有价值的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d476/7033114/414a33ea36eb/41392_2019_103_Fig8_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d476/7033114/161a630a298f/41392_2019_103_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d476/7033114/1bc6a53598c5/41392_2019_103_Fig6_HTML.jpg
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