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TDO2 and tryptophan metabolites promote kynurenine/AhR signals to facilitate glioma progression and immunosuppression.

ABSTRACT: Tumor cells exhibit enhanced uptake and processing of nutrients to fulfill the demands of rapid growth of tumor tissues. Tryptophan metabolizing dioxygenases are frequently up-regulated in several tumor types, which has been recognized as a crucial determinant in accelerated tumor progression. In our study, we explored the specific role of tryptophan 2,3-dioxygenase 2 (TDO2) in glioma progression. Analysis of mRNA profiles in 325 glioma patients based on the rich set of CCGA database was performed, which revealed that high TDO2 expression was tightly correlated with poor prognosis in glioma patients. TDO2 increased intracellular levels of tryptophan metabolism in the kynurenine (Kyn) pathway in vitro and in vivo, resulting in sustained glioma cell proliferation. Mechanistically, overexpression of TDO2 promoted the secretion of Kyn, which in turn stimulated the activation of the aryl hydrocarbon receptor (AhR)/AKT signaling pathway, resulting in heightened proliferative properties and tumorigenic potential in glioma cells. Meanwhile, Kyn produced by tumor cells further suppressed the proliferation of functional T cells, thereby resulting in immunosuppression and enhanced tumor growth in glioma. Our study showed that TDO2-induced increase in tryptophan metabolite Kyn played a pivotal role in glioma development via the AhR/AKT pro-survival signals and immunosuppressive effects, suggesting that the use of TDO2 inhibitors in combination with chemotherapy may be a novel strategy to effectively and synergistically eliminate glioma cells.

SUBMITTER: Zhong C

PROVIDER: S-EPMC9251687 | biostudies-literature |

REPOSITORIES: biostudies-literature

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MED12 mutation activates the tryptophan/kynurenine/AHR pathway to promote growth of uterine leiomyomas

Project description:Uterine leiomyoma (LM) is the most common tumor in women. Estrogen and progesterone, via their receptors ERα and PR, play essential roles in LM growth. Mediator complex subunit 12 (MED12) mutations occur in 70% of all LM and are thought to drive tumor growth in a steroid hormone-dependent manner; however, the mechanisms remain unclear. Here, we performed ChIP-seq (ERα, PR, and MED12) and RNA-seq on LM expressing mutant MED12 (mut-MED12) or wild-type MED12 and matched myometrium. Mut-MED12 altered PR and chromatin interaction landscapes, with significant PR-binding site loss in proximal promoter regions in mut-MED12 LM. Integration of cistrome and transcriptome data identified tryptophan 2,3-dioxygenase (TDO2) as a PR and MED12 target gene, which was aberrantly upregulated in mut-MED12 LM. Kynurenine, the catabolic product of TDO2, was significantly elevated in mut-MED12 LM. Tryptophan or kynurenine treatment of primary LM cells activated the aryl hydrocarbon receptor (AHR) pathway, increased cell proliferation, and inhibited apoptosis; blocking the TDO2-kynurenine-AHR pathway by siRNA knockdown or pharmacologic inhibition abolished these effects. Mut-MED12 LM cells showed higher sensitivity to these treatments. These findings suggest that activation of the TDO2-kynurenine-AHR pathway in mut-MED12 LM induces tumor growth, and may inform the development of targeted treatments and precision medicine in LM.

2023-05-01 | GSE204968 | GEO

The impact of bariatric surgery on serum tryptophan-kynurenine pathway metabolites.

Project description:This study aims to explore the immediate effects of bariatric surgery on serum tryptophan-kynurenine pathway metabolites in individuals with type 2 diabetes and BMI > 30. With the goal of providing insight into the link between tryptophan pathway metabolites, type 2 diabetes, and chronic obesity-induced inflammation. This longitudinal study included 20 participants. Half were diagnosed with type 2 diabetes. 11 and 9 underwent RYGB and SG respectively. Blood samples were obtained at pre-operative and 3 months post-operative timepoints. Tryptophan and downstream metabolites of the kynurenine pathway were quantified with an ultrahigh-performance liquid chromatography tandem mass spectrometry with electrospray ionisation method. At 3 months post-operation, RYGB led to significant reductions in tryptophan, kynurenic acid and xanthurenic acid levels when compared to baseline. Significant reductions of the same metabolites after surgery were also observed in individuals with T2D irrespective of surgical procedure. These metabolites were significantly correlated with serum HbA1c levels and BMI. Bariatric surgery, in particular RYGB reduces serum levels of tryptophan and its downstream kynurenine metabolites. These metabolites are associated with T2D and thought to be potentially mechanistic in the systemic processes of obesity induced inflammation leading to insulin resistance. Its reduction after surgery is associated with an improvement in glycaemic control (HbA1c).

| S-EPMC8741964 | biostudies-literature

Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites.

Project description:Metabolites of the kynurenine pathway (KP) of tryptophan (TRP) degradation have been closely linked to the pathogenesis of several neurodegenerative disorders. Recent work has highlighted the therapeutic potential of inhibiting two critical regulatory enzymes in this pathway-kynurenine-3-monooxygenase (KMO) and tryptophan-2,3-dioxygenase (TDO). Much evidence indicates that the efficacy of KMO inhibition arises from normalizing an imbalance between neurotoxic [3-hydroxykynurenine (3-HK); quinolinic acid (QUIN)] and neuroprotective [kynurenic acid (KYNA)] KP metabolites. However, it is not clear if TDO inhibition is protective via a similar mechanism or if this is instead due to increased levels of TRP-the substrate of TDO. Here, we find that increased levels of KYNA relative to 3-HK are likely central to the protection conferred by TDO inhibition in a fruit fly model of Huntington's disease and that TRP treatment strongly reduces neurodegeneration by shifting KP flux toward KYNA synthesis. In fly models of Alzheimer's and Parkinson's disease, we provide genetic evidence that inhibition of TDO or KMO improves locomotor performance and ameliorates shortened life span, as well as reducing neurodegeneration in Alzheimer's model flies. Critically, we find that treatment with a chemical TDO inhibitor is robustly protective in these models. Consequently, our work strongly supports targeting of the KP as a potential treatment strategy for several major neurodegenerative disorders and suggests that alterations in the levels of neuroactive KP metabolites could underlie several therapeutic benefits.

| S-EPMC4868470 | biostudies-literature

MED12 Mutation Activates Tryptophan-Kynurenine-AHR pathway and Promotes Cell Growth in Human Uterine Leiomyoma.

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-05-01 | GSE204970 | GEO

TDO2 Promotes the EMT of Hepatocellular Carcinoma Through Kyn-AhR Pathway.

Project description:Tryptophan 2,3-dioxygenase (TDO2), an enzyme involved in tryptophan (Trp) metabolism has been linked with some malignant traits of various cancers. Kyn, the main product of Trp metabolism pathway catalyzed by TDO2 and indoleamine 2,3-dioxygenase (IDO) in tumor cells, was also demonstrated to activate aryl hydrocarbon receptor (AhR), which may regulate cancer growth and invasion in some malignancies. However, whether TDO2 participates in the metastasis and invasion of HCC has not been explored before. The underlying mechanism played by TDO2 in this process still requires further investigation. Here, we demonstrated that overexpression of TDO2 correlates with advanced stage or malignant traits in HCC patients. Knockdown or inhibition of TDO2 suppressed the migration and invasion of HCC cells in vitro and in vivo. Epithelial to mesenchymal transition (EMT) is an essential program happened in the initial phase of cancer metastasis. We found that in HCC cells, TDO2 promoted the EMT process evidenced by altered levels of biomarkers for EMT. Mechanically, TDO2 regulated the Kyn production in HCC cell via activated aryl hydrocarbon receptor (AhR). Together, these results indicate that TDO2 promotes the EMT of hepatocellular carcinoma through activating Kyn-AhR pathway, thereby participating in the metastasis and invasion of HCC.

| S-EPMC7851084 | biostudies-literature

Comprehensive behavioral analysis of tryptophan 2,3-dioxygenase (Tdo2) knockout mice.

Project description:Aims: Tryptophan 2,3-dioxygenase (TDO2) is an initial rate-limiting enzyme of the kynurenine (Kyn) pathway in tryptophan (Trp) metabolism. The Trp-degrading enzymes, TDO2 and indoleamine 2,3-dioxygenase, are activated by stress and/or inflammation. Dysregulation of Trp metabolism, which causes shifts in the balance between Kyn and serotonin (5-HT) pathways, is associated with psychiatric and neurological disorders. In genetic studies, single-nucleotide polymorphisms in the TDO2 gene were shown to be involved in psychiatric disorders, such as schizophrenia and depression. It has been reported that targeted deletion of the Tdo2 gene in mice resulted in reduced anxiety-like behavior, enhanced exploratory activity and cognitive performance, and increased levels of Trp and 5-HT in the hippocampus and midbrain. However, the effect of Tdo2 gene deletion on behavioral phenotypes has not yet been investigated extensively.Materials & methods: We conducted tests to further examine the behavioral effects of knockout (KO) of Tdo2 in mice.Results: Deletion of Tdo2 resulted in seemingly lower anxiety-like behavior, higher locomotor activity, and abnormal gait pattern in mice, though none of them reached study-wide statistical significance. Tdo2 deficiency had no significant effects on other behaviors, such as prepulse inhibition, and depression-like and social behaviors.Discussion and conclusion: He lack of clear phenotypes in Tdo2KO mice in this study might be due to the absence of stress and inflammatory conditions, which could induce expression of Tdo2 mRNA. Further studies are necessary to elucidate the roles of Tdo2 in behavioral phenotypes related to psychiatric disorders.

| S-EPMC7292271 | biostudies-literature

Aminoisoxazoles as Potent Inhibitors of Tryptophan 2,3-Dioxygenase 2 (TDO2).

Project description:Tryptophan 2,3-dioxygenase 2 (TDO2) catalyzes the conversion of tryptophan to the immunosuppressive metabolite kynurenine. TDO2 overexpression has been observed in a number of cancers; therefore, TDO inhibition may be a useful therapeutic intervention for cancers. We identified an aminoisoxazole series as potent TDO2 inhibitors from a high-throughput screen (HTS). An extensive medicinal chemistry effort revealed that both the amino group and the isoxazole moiety are important for TDO2 inhibitory activity. Computational modeling yielded a binding hypothesis and provided insight into the observed structure-activity relationships. The optimized compound 21 is a potent TDO2 inhibitor with modest selectivity over indolamine 2,3-dioxygenase 1 (IDO1) and with improved human whole blood stability.

| S-EPMC5949840 | biostudies-literature

Effects of Tryptophan Supplementation and Exercise on the Fate of Kynurenine Metabolites in Mice and Humans.

Project description:The kynurenine pathway of tryptophan (TRP) degradation (KP) generates metabolites with effects on metabolism, immunity, and mental health. Endurance exercise training can change KP metabolites by changing the levels of KP enzymes in skeletal muscle. This leads to a metabolite pattern that favors energy expenditure and an anti-inflammatory immune cell profile and reduces neurotoxic metabolites. Here, we aimed to understand if TRP supplementation in untrained vs. trained subjects affects KP metabolite levels and biological effects. Our data show that chronic TRP supplementation in mice increases all KP metabolites in circulation, and that exercise reduces the neurotoxic branch of the pathway. However, in addition to increasing wheel running, we did not observe other effects of TRP supplementation on training adaptations, energy metabolism or behavior in mice. A similar increase in KP metabolites was seen in trained vs. untrained human volunteers that took a TRP drink while performing a bout of aerobic exercise. With this acute TRP administration, TRP and KYN were higher in the trained vs. the untrained group. Considering the many biological effects of the KP, which can lead to beneficial or deleterious effects to health, our data encourage future studies of the crosstalk between TRP supplementation and physical exercise.

| S-EPMC8400416 | biostudies-literature

MED12 Mutation Activates Tryptophan-Kynurenine-AHR pathway and Promotes Cell Growth in Human Uterine Leiomyoma [RNA-seq]

2023-05-01 | GSE204969 | GEO

Studies with tryptophan metabolites in vitro. Kynurenine metabolism in kidneys of mice infested with Schistosoma mansoni.

Project description:The conversion in vitro of kynurenine into kynurenic acid and anthranilic acid in both normal kidneys and those obtained from mice infested with Schistosoma mansoni was investigated. Normal mouse kidneys seem to possess an excess of functional pyridoxal phosphate over those obtained from infested mice. Kynureninase and kynurenine transaminase in the latter kidneys are more easily inhibited by deoxypyridoxal phosphate and tartar emetic, indicating low stores of active pyridoxal phosphate. The possible implication of these findings in relation to the role of the kidneys in producing abnormal patterns of tryptophan metabolism and possibly contributing to the production of bladder tumours in bilharzial patients is discussed.

| S-EPMC1186946 | biostudies-other

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