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

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.

FTO interacts with FOXO3a to enhance its transcriptional activity and inhibits aggression in gliomas

Dear Editor,Gliomas represent the most common primary brain tumors in adults and few targeted therapies are available.Thus,it’s imperative to explore novel target genes in gliomas.Fat mass and obesity-associated(FTO)gene encodes an alphaketoglutarate-dependent dioxygenase,which demethylates N6-methyladenosine on single-strand RNA.1 FTO is highly expressed in the brain but its potential contribution to gliomas is unknown.FOXO3a belongs to the forkhead family of transcription factors and it mediates important cellular processes like apoptosis and proliferation by regulating its target gene expression.2 Interestingly,genetic variants of FOXO33 and FTO4 are associated with longevity in human,suggesting that FTO and FOXO3a might share convergent effects in biological processes.Thus,we investigated the involvement of potential FTO–FOXO3a interaction in gliomas.

MEK2 is a prognostic marker and potential chemo-sensitizing target for glioma patients undergoing temozolomide treatment

Although temozolomide （TMZ） is the first-line chemotherapeutic agent for glioblastoma, it is often non-curative due to drug resistance. To overcome the resistance of glioblastoma cells to TMZ, it is imperative to identity prognostic markers for outcome prediction and to develop chemo-sensitizing agents. Here, the gene expression profiles of TMZ-resistant and TMZ-sensitive samples were compared by microarray analysis, and mitogen-activated protein kinase kinase 2 （MEK2） was upregulated specifically in resistant glioma cells but not in sensitive tumor cells or non-tumor tissues. Moreover, a comprehensive analysis of patient data revealed that the increased level of MEK2 expression correlated well with the advancement of glioma grade and worse prognosis in response to TMZ treatment. Furthermore, reducing the level of MEK2 in U251 glioma cell lines or xenografted glioma models through shRNA-mediated gene knockdown inhibited cell proliferation and enhanced the sensitivity of cells toward TMZ treatment. Further analysis of tumor samples from glioma patients by real-time PCR indicated that an increased MEK2 expression level was closely associated with the activation of many drug resistance genes. Finally, these resistance genes were downregulated after MEK2 was silenced in vitro, suggesting that the mechanism of MEK2-induced chemo-resistance could be mediated by the transcriptional activation of these resistance genes. Collectively, our data indicated that the expression level of MEK2 could serve as a prognostic marker for glioma chemotherapy and that MEK2 antagonists can be used as chemo-sensitizers to enhance the treatment efficacy of TMZ.

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

In the process of collating the raw data,the authors noticed the inadvertent mistakes in Fig.4h&6g that need to be corrected.The correct data are provided as follows.The key findings of the article are not affected by the corrections.We apologize for the inadvertent mistakes.The authors mistakenly placed the wrong representative image showing the invasion ability of U87MG cells in the IFN-γ+1-MT group.The correct version of Fig.4h is shown above.