Tryptophan: Its Metabolism along the Kynurenine, Serotonin, and Indole Pathway in Malignant Melanoma

Hubková, Beáta; Valko-Rokytovská, Marcela; Čižmárová, Beáta; Zábavníková, Marianna; Mareková, Mária; Birková, Anna

doi:10.3390/ijms23169160

Cited by 14 publications

(12 citation statements)

References 38 publications

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“…[1,2] The tumor microenvironment (TME) of MM is characterized by various distinct features, including overexpression of a cornucopia of immune suppressive cytokines [3] and an upregulation of different immune checkpoints, which promote tumorigenesis, facilitate immune evasion, and suppress T cell-mediated antitumor responses. [4,5] Furthermore, another characteristic feature of MM is the excessive consumption of arginine (Arg), [6] glutamine (Gln) [7] and tryptophan (Trp) [8] amino acids as a result of reprogrammed metabolism. This overconsumption of nutrients deprives the immune cells of the essential nutrients required for their proliferation and differentiation.…”

Section: Introductionmentioning

confidence: 99%

Nano‐Mediated PDT as a Multifunctional Immunomodulatory Agent in the Intricate Milieu of Melanoma

Sebak,

Abdel‐Halim,

Abdelrahman

et al. 2024

Advanced Therapeutics

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The complexity of the tumor microenvironment (TME) and nutrient competition represent the main causes of therapy resistance in cancers, including malignant melanoma (MM). Photodynamic therapy (PDT), through a cascade of events including its ability to induce significant immune responses, causes tumor eradication. However, the high pigmentation level of melanoma, lack of adequate accumulation of photosensitizers (PSs) in the target tissue as well as their nonspecific toxicity represent three main obstacles to obtaining satisfactory responses in melanoma. To prevail over these challenges, this study employed a depigmentation strategy followed by a nano‐mediated topical application of PDT using a chlorophyllin derivative as PS, focusing on evaluation of the immunomodulatory and metabolic regulatory axes of PDT in melanoma. Photo‐immunomodulation was assessed in a melanoma mouse model using a nanocarrier system of the PS. Markers of the immunosuppressive microenvironment and T cell exhaustion, as independent immune hallmarks, were quantified. The histopathology of spleen and skin/tumor was evaluated. The amino acid profile was quantified from normal skin or tumor biopsies using UHPLC‐MS/MS. Around 80% of the 300 nm transethosomal ferrous chlorophyllin (fC‐TEs) were retained in the tumor over 24 h upon topical application. Arbutin 2% gel not only decreased the melanin content of tumors, but also regulated the expression of interleukin 12 (IL‐12), IL‐10, transforming growth factor beta (TGF‐β) and tumor necrosis factor alpha (TNF‐α). Additionally, the nano‐mediated PDT strategy decreased the expression of programmed cell death protein 1 (PD‐1) & its ligand 1 (PD‐L1) and reduced the activity of arginase 1 (Arg1) through an upregulation of miRNA155. A mild recruitment of megakaryocytes (MKs) was observed in the spleen of the PDT group. This special localization of MKs depicts effector immune properties. Lastly, the combination of PDT and arbutin restored the normal tissue levels of arginine (Arg), glutamine (Gln) and lavished those of tryptophan (Trp). Nano‐mediated PDT represents a novel immunotherapeutic approach in melanoma by a triple modulation of the immune suppressive TME, immune checkpoint signaling, and reprogrammed tumor metabolism.This article is protected by copyright. All rights reserved

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Section: Introductionmentioning

confidence: 99%

Nano‐Mediated PDT as a Multifunctional Immunomodulatory Agent in the Intricate Milieu of Melanoma

Sebak,

Abdel‐Halim,

Abdelrahman

et al. 2024

Advanced Therapeutics

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“…The Trp-KYN metabolic system, closely associated with 5-HT metabolism, plays a pivotal role in the production of prooxidants and antioxidants, regulation of the immune system, and the balance between neurotoxicity and neuroprotection (54,55). Approximately 2% of L-Trp undergoes metabolism through the 5HT metabolic pathway; however, over 90% of Trp is catabolized through the KYN route, which safely to say that it governs Trp metabolism (Figure 1, a,b) (56). Various factors, including stress, inflammation, and the gut microbiome, influence this system (57)(58)(59).…”

Section: Introductionmentioning

confidence: 99%

Oxidative and Excitatory Neurotoxic Stresses in CRISPR/Cas9-Induced Kynurenine Aminotransferase Knock-Out Mice: A Novel Model for Experience-Based Depression and Post-traumatic Stress Disordertabolism: Insights From Novel Kynurenine Aminotransferase

Szabó,

Galla,

Spekker

et al. 2024

Preprint

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Memory and emotion are highly vulnerable to psychiatric disorders like post-traumatic stress disorder (PTSD), which has been linked to serotonin (5-HT) metabolism disruptions. In fact, over 90% of the 5-HT precursor tryptophan (Trp) is metabolized via the Trp-kynurenine (KYN) meta-bolic pathway, producing a variety of bioactive molecules. The aadat (kat2) gene encodes mito-chondrial kynurenine aminotransferase (KAT) isotype 2, responsible for kynurenic acid (KYNA) production. Little is known about its role in behavior. In CRISPR/Cas9-induced aadat knockout (kat2−/−) mice, we examined the effects on emotion, memory, motor function, Trp and its metabolite levels, enzyme activities in the plasma and the urine of 8-week-old males compared to wild-type mice. Transgenic mice showed more depressive-like behaviors in the forced swim test, but not in the tail suspension, anxiety, or memory tests. They also had fewer center field and corner entries, shorter walking distances, and fewer jumping counts in the open field test. Plasma metabolite levels are generally consistent with those of urine: KYN, antioxidant KYNs, 5-hydroxyindolacetic acid, and indole-3-acetic acid levels are lower; enzyme activities in KATs, kynureninase, and monoamine oxidase/aldehyde dehydrogenase are lower, but kynurenine 3-monooxygenase is higher; and ox-idative stress and excitotoxicity indices are higher. Transgenic mice show depression-like behavior in a learned helplessness model, emotional indifference, and motor deficits, coupled with a decrease in KYNA, a shift of Trp metabolism toward the KYN-3-HK pathway, and a partial decrease in the gut microbial Trp-indole pathway metabolite. This is the first evidence that deleting the aadat gene causes depression-like behaviors that are unique to despair experience, which appears to be linked to excitatory neurotoxic and oxidative stresses. This may lead to the development of a double-hit preclinical model in experience-based depression, better understanding of these complex condi-tions, and more effective therapeutic strategies by elucidating the relationship between Trp me-tabolism and PTSD pathogenesis.

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“…Tryptophan, which is involved in a wide range of benign and malignant disorders, is metabolised by three pathways: The Kynurenine pathway (KP), with degradation mainly in the liver, is associated with neuroactive and immunomodulatory effects; the Serotonin pathway, with degradation in the gut, is associated with behavioural and neuroendocrine functions; and the Indole-Pyruvate pathway, with degradation by the gut microbiota, is associated with intestinal physiology. The interplay between the pathways is complex; all pathways might be involved in one disease [1].…”

Section: Introductionmentioning

confidence: 99%

APOE Polymorphism Is Associated with Changes in the Kynurenine Pathway

Farup,

Rootwelt,

Hestad

2023

Genes

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Background: APOE polymorphism and the Kynurenine pathway (KP) are associated with many disorders, but little is known about associations between APOE polymorphism and the KP. This study explored the associations between the KP and APOE polymorphism in disorders associated with APOE polymorphism and changes in the KP. Methods: Subjects with morbid obesity before and after bariatric surgery (numbers 139 and 95, respectively), depression (number 49), and unspecified neurological symptoms (number 39) were included. The following grouping of the APOE genotypes was used: E2 = ɛ2ɛ2 + ɛ2ɛ3, E3 = ɛ3ɛ3 + ɛ2ɛ4, and E4 = ɛ3ɛ4 + ɛ4ɛ4. The KP metabolites Tryptophan, Kynurenine, Kynurenic acid, Quinolinic acid, and Xanthurenic acid were quantified in serum. Results: The main findings were a significant positive association between E3 and Quinolinic acid (difference between E3 and E2E4: 12.0 (3.5; 18.6) ng/mL); p = 0.005), and a negative association between E4 and Kynurenine (difference between E4 and E2E3: −31.3 (−54.2; −3.2) ng/mL; p = 0.008). Quinolinic acid has been ascribed neurotoxic and inflammatory effects, and Kynurenine is a marker of inflammation. Conclusions: The findings indicate that APOE polymorphism might cause changes in the KP that contribute to the disease. Inflammation could be the link between APOE and the KP.

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Tryptophan: Its Metabolism along the Kynurenine, Serotonin, and Indole Pathway in Malignant Melanoma

Cited by 14 publications

References 38 publications

Nano‐Mediated PDT as a Multifunctional Immunomodulatory Agent in the Intricate Milieu of Melanoma

Nano‐Mediated PDT as a Multifunctional Immunomodulatory Agent in the Intricate Milieu of Melanoma

Oxidative and Excitatory Neurotoxic Stresses in CRISPR/Cas9-Induced Kynurenine Aminotransferase Knock-Out Mice: A Novel Model for Experience-Based Depression and Post-traumatic Stress Disordertabolism: Insights From Novel Kynurenine Aminotransferase

APOE Polymorphism Is Associated with Changes in the Kynurenine Pathway

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