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.
Highlights
Gliomas are the most common primary central nervous system tumors in the brain.[1]
In IDO1, IDO2, and TDO-expressing glioma edema in the IDO1−, IDO1 +, TDO−, and TDO + groups were (Fig. 1a, b, d) rather than IDO2 (Fig. 1a, c) was positively correlated with the pathologic grades
The IDO1/TDO–Kyn–aryl hydrocarbon receptor (AhR) signaling pathway modulated glioma cell migration and invasion via aquaporin 4 (AQP4) The preceding results showed that the expression of IDO1 and TDO was positively related to the expression of AQP4, while Kyn produced by IDO1 and TDO upregulated the expression of AhR, so we examined whether and how the identified IDO1/ TDO–Kyn–AhR signaling pathway regulated AQP4 expression
Summary
Gliomas are the most common primary central nervous system tumors in the brain.[1]. Despite advances in surgical resection, irradiation, and chemotherapy, the fatality rate of patients with gliomas remains high, and the survival time is only ~15 months for newly diagnosed patients.[2]. Recent studies suggest that the kynurenine pathway (KP), the major route of L-tryptophan (Trp) catabolism leading to the production of L-kynurenine (Kyn), plays an important role in the pathogenesis of gliomas.[5,6,7,8,9,10] The enzymes indoleamine 2,3-
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