The mechanism by which IDO1 inhibitors play a role in gliomas.

Glioma is the most common primary central nervous system tumor, and its poor prognosis is closely related to glioma cell migration and invasion.
tryptophan dioxygenase (IDO, TDO) activates the metabolic pathway of canine urea (KP), causing L-trypyrine (Trp) to be converted into L-canine urea (Kyn).
Kyn is an endogenetic ligation of aromatic hydrocarbons (AhR), and TDO activates AhR through Kyn to promote glioma growth.
, the mechanism by which IDO functions has not yet been clarified.
writing in the February 2020 online issue of Signal Transduction and Target Therapy, Lisha Du of Fudan University's School of Life Sciences reported that Professor Yang Qing's team explored the mechanisms of IDO's role in glioma by detecting the expression and activity of IDO1, IDO2, and TDO in different levels of glioma specimens and serums.
study found that the expression of IDO1 and TDO was positively correlation with glioma pathological grading, while IDO2 did not.
Trp concentration was significantly lower than that of 5 low-level gliomas of Grade III/IV in 11 cases.
, the concentration of glioma Trp was significantly lower than in patients with non-glioma.
the Kyn/Trp ratio was significantly higher in patients with high-level gliomas than in patients with low-level or non-glioma groups.
data show that both IDO1 and TDO are associated with the malignancy of gliomas (Figure 1).
Figure 1. The expression and activity of IDO1/TDO were positively correlant with the pathological grading of glioma.
authors found that expressions of IDO1 and TDO were positively correled with the Ki67 index, which was positively correled with the pathological classification of gliomas and negatively cored with overall survival.
the overall survival rate of patients with IDO1-positive, TDO-positive or IDO1 and TDO-positive patients decreased significantly, and the expression of IDO1/TDO was negatively correlated with the prognosis of glioma patients: the expression of IDO2 was independent of the overall survival rate of Ki67 index and glioma patients.
further study by the authors found that the expression of water phase channel protein 4 (AQP4) in patients with IDO1 or TDO high expression group increased significantly compared to the low expression group of IDO1 or TDO, and that the expression of IDO1/TDO was positively correlation with the expression of water phase channel protein 4 (AQP4) in patients with glioma.
previous literature has reported that AQP4 ascension is closely related to the formation of cerebral edema of malignant gliomas, which contributes to glioma cell invasion, indicating that IDO1 and TDO may be involved in the migration and invasion of glioma cells.
by the authors confirmed that IDO1/TDO migrates and invades glioma cells through Kyn.
IDO1 inhibitor 1-MT does not inhibit IFN-1-induced IDO1 expression, but it can inhibit the migration and invasion of glioma cells promoted by IFN-1, and over-expression of IDO1/TDO in U87 cells can significantly improve cell migration and invasion.
the use of RNA interference technology to remove TDO expression, significantly reduced U87 cell migration and invasive ability.
at the same time, Kyn promotes U87 cell migration and invasion, and when supplementing exogenic Kyn, the migration and invasive capacity caused by IDO1 inhibition or TDO knock-out can be reversed, indicating that IDO1 and TDO can mediate the migration and invasion of U87 cells through Kyn.
also found that IDO1/TDO was expressed through Kyn's increased glioma cell AhR.
in U87 cells, over-expression IDO1 can significantly increase the expression of AhR, 1-MT inhibition of IDO1 activity significantly reduce ahR expression.
in U87 cells, over-expression of TDO can also significantly increase AhR, knocking out TDO significantly reduces AhR expression.
in U87 cells over-expressed by IDO1/TDO, Kyn expression increased significantly, while Kyn expression decreased significantly when IDO1 activity was inhibited or TDO was knocked out.
significantly increased AhR expression after treating U87 cells with Kyn, which is shifted from cytoma to the nucleus, indicating that IDO1 and TDO are increased by Kyn to increase the expression of glioma cell AhR.
as mentioned earlier, AQP4 is involved in glioma cell invasion, is this phenomenon mediated through the IDO1/TDO-Kyn-AhR signaling path? In U87 cells, over-expression of TDO, or Kyn treatment, significantly increased AQP4 expression, and vice versa.
inhibition of AhR activity reduces AQP4 expression, while Kyn treatment increases the expression of AhR's target genes CYP1A1 and CYP1B1, Kyn helps AhR bind to multiple DRE bits of AQP4 promoters.
results show that IDO1 and TDO use Kyn to promote AhR in conjunction with AQP4 to improve their expression.
in U87 cells, over-expression of AQP4 or treatment with Kyn can promote its migration and invasion, but Kyn treatment does not reverse the effects of AhR inhibition or AQP4 knock-out.
1-MT inhibits IFN-gamma-induced actin F-actin expression, IDO1 and TDO over-expression, as well as Kyn treatment can increase F-actin expression, knocking out TDO inhibits F-actin expression, indicating that IDO1/TDO-Kyn-AhR-AQP4 signaling path is playing an important role in regulating glioma cell migration and invasion.
the authors then used MRI imaging to explore the role of IDO1/TDO inhibitors in animal experiments.
MRI imaging showed that the IDO1/TDO inhibitor RY103 significantly reduced the volume of animal gliomas in the in-place transplant model, and the serum Trp level of the RY103 treatment group was similar to that of the control group, but the ratio of Kyn level to Kyn/Trp in the RY103 treatment group was significantly lower than that of the control group.
, RY103 can significantly inhibit IDO1 and TDO activity of gliomas in animals.
, IDO1, TDO, AhR, and AQP4 expressions in the RY103 processing group were significantly lower than in the control group.
, the survival time of the RY103 group was significantly longer.
, animal experiments have shown that inhibiting IDO1/TDO blocks IDO1/TDO-Kyn-AhR-AQP4 signaling path path, thereby inhibiting glioma cell growth.
conclusions, the study found that in addition to TDO, IDO1 also played an important role in cell migration and invasion of gliomas.
IDO1/TDO-Kyn-AhR-AQP4 signaling path is a new mechanism for regulating the malignant biological behavior of gliomas, and the treatment of gliomas with inhibitors targeting IDO1 and TDO should have great potential.
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