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Zhang HL, Zhao R, Wang D, Mohd Sapudin SN, Yahaya BH, Harun MSR, Zhang ZW, Song ZJ, Liu YT, Doblin S, Lu P. Candida albicans and colorectal cancer: A paradoxical role revealed through metabolite profiling and prognostic modeling. World J Clin Oncol 2025; 16:104182. [PMID: 40290696 PMCID: PMC12019262 DOI: 10.5306/wjco.v16.i4.104182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 01/11/2025] [Accepted: 01/23/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Emerging evidence implicates Candida albicans (C. albicans) in human oncogenesis. Notably, studies have supported its involvement in regulating outcomes in colorectal cancer (CRC). This study investigated the paradoxical role of C. albicans in CRC, aiming to determine whether it promotes or suppresses tumor development, with a focus on the mechanistic basis linked to its metabolic profile. AIM To investigate the dual role of C. albicans in the development and progression of CRC through metabolite profiling and to establish a prognostic model that integrates the microbial and metabolic interactions in CRC, providing insights into potential therapeutic strategies and clinical outcomes. METHODS A prognostic model integrating C. albicans with CRC was developed, incorporating enrichment analysis, immune infiltration profiling, survival analysis, Mendelian randomization, single-cell sequencing, and spatial transcriptomics. The effects of the C. albicans metabolite mixture on CRC cells were subsequently validated in vitro. The primary metabolite composition was characterized using liquid chromatography-mass spectrometry. RESULTS A prognostic model based on five specific mRNA markers, EHD4, LIME1, GADD45B, TIMP1, and FDFT1, was established. The C. albicans metabolite mixture significantly reduced CRC cell viability. Post-treatment analysis revealed a significant decrease in gene expression in HT29 cells, while the expression levels of TIMP1, EHD4, and GADD45B were significantly elevated in HCT116 cells. Conversely, LIME1 expression and that of other CRC cell lines showed reductions. In normal colonic epithelial cells (NCM460), GADD45B, TIMP1, and FDFT1 expression levels were significantly increased, while LIME1 and EHD4 levels were markedly reduced. Following metabolite treatment, the invasive and migratory capabilities of NCM460, HT29, and HCT116 cells were reduced. Quantitative analysis of extracellular ATP post-treatment showed a significant elevation (P < 0.01). The C. albicans metabolite mixture had no effect on reactive oxygen species accumulation in CRC cells but led to a reduction in mitochondrial membrane potential, increased intracellular lipid peroxidation, and induced apoptosis. Metabolomic profiling revealed significant alterations, with 516 metabolites upregulated and 531 downregulated. CONCLUSION This study introduced a novel prognostic model for CRC risk assessment. The findings suggested that the C. albicans metabolite mixture exerted an inhibitory effect on CRC initiation.
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Affiliation(s)
- Hao-Ling Zhang
- Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453000, Henan Province, China
- Department of Biomedical Science, Universiti Sains Malaysia, Pinang 13200, Malaysia
| | - Rui Zhao
- Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Di Wang
- Department of Biomedical Science, Universiti Sains Malaysia, Pinang 13200, Malaysia
| | - Siti Nurfatimah Mohd Sapudin
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang 13200, Malaysia
| | - Badrul Hisham Yahaya
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang 13200, Malaysia
| | - Mohammad Syamsul Reza Harun
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang 13200, Malaysia
| | - Zhong-Wen Zhang
- School of Public Health, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Zhi-Jing Song
- Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Yan-Ting Liu
- Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453000, Henan Province, China
| | - Sandai Doblin
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang 13200, Malaysia
| | - Ping Lu
- Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453000, Henan Province, China
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Lu Z, Zhang C, Zhang J, Su W, Wang G, Wang Z. The Kynurenine Pathway and Indole Pathway in Tryptophan Metabolism Influence Tumor Progression. Cancer Med 2025; 14:e70703. [PMID: 40103267 PMCID: PMC11919716 DOI: 10.1002/cam4.70703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 01/22/2025] [Accepted: 02/04/2025] [Indexed: 03/20/2025] Open
Abstract
Tryptophan (Trp), an essential amino acid, is solely acquired through dietary intake. It is vital for protein biosynthesis and acts as a precursor for numerous key bioactive compounds. The Kynurenine Pathway and the Indole Pathway are the main metabolic routes and are extensively involved in the occurrence and progression of diseases in the digestive, nervous, and urinary systems. In the Kynurenine Pathway, enzymes crucial to tryptophan metabolism, indoleamine-2,3-dioxygenase 1 (IDO1), IDO2, and Trp-2,3-dioxygenase (TDO), trigger tumor immune resistance within the tumor microenvironment and nearby lymph nodes by depleting Trp or by activating the Aromatic Hydrocarbon Receptor (AhR) through its metabolites. Furthermore, IDO1 can influence immune responses via non-enzymatic pathways. The Kynurenine Pathway exerts its effects on tumor growth through various mechanisms, including NAD+ regulation, angiogenesis promotion, tumor metastasis enhancement, and the inhibition of tumor ferroptosis. In the Indole Pathway, indole and its related metabolites are involved in gastrointestinal homeostasis, tumor immunity, and drug resistance. The gut microbiota related to indole metabolism plays a critical role in determining the effectiveness of tumor treatment strategies and can influence the efficacy of immunochemotherapy. It is worth noting that there are conflicting effects of the Kynurenine Pathway and the Indole Pathway on the same tumor phenotype. For example, different tryptophan metabolites affect the cell cycle differently, and indole metabolism has inconsistent protective effects on tumors in different regions. These differences may hold potential for enhancing therapeutic efficacy.
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Affiliation(s)
- Zhanhui Lu
- Department of Medical Oncology, Longhua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Shanghai University of Traditional Chinese MedicineShanghaiChina
- Cancer Institute, Longhua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Chengcheng Zhang
- Department of Medical Oncology, Longhua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Shanghai University of Traditional Chinese MedicineShanghaiChina
- Cancer Institute, Longhua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Jia Zhang
- Provincial Hospital Affiliated to Shandong First Medical UniversityJinanShandongChina
| | - Wan Su
- Department of Medical Oncology, Longhua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Guoying Wang
- Department of Critical Care MedicineThe Second People's Hospital of DongyingDongyingShandongChina
| | - Zhongqi Wang
- Department of Medical Oncology, Longhua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
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Damerell V, Klaassen‐Dekker N, Brezina S, Ose J, Ulvik A, van Roekel EH, Holowatyj AN, Baierl A, Böhm J, Bours MJL, Brenner H, de Wilt JHW, Grady WM, Habermann N, Hoffmeister M, Keski‐Rahkonen P, Lin T, Schirmacher P, Schrotz‐King P, Ulrich AB, van Duijnhoven FJB, Warby CA, Shibata D, Toriola AT, Figueiredo JC, Siegel EM, Li CI, Gsur A, Kampman E, Schneider M, Ueland PM, Weijenberg MP, Ulrich CM, Kok DE, Gigic B, FOCUS Consortium. Circulating tryptophan-kynurenine pathway metabolites are associated with all-cause mortality among patients with stage I-III colorectal cancer. Int J Cancer 2025; 156:552-565. [PMID: 39308420 PMCID: PMC11621991 DOI: 10.1002/ijc.35183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 07/22/2024] [Accepted: 08/02/2024] [Indexed: 09/28/2024]
Abstract
Alterations within the tryptophan-kynurenine metabolic pathway have been linked to the etiology of colorectal cancer (CRC), but the relevance of this pathway for prognostic outcomes in CRC patients needs further elucidation. Therefore, we investigated associations between circulating concentrations of tryptophan-kynurenine pathway metabolites and all-cause mortality among CRC patients. This study utilizes data from 2102 stage I-III CRC patients participating in six prospective cohorts involved in the international FOCUS Consortium. Preoperative circulating concentrations of tryptophan, kynurenine, kynurenic acid (KA), 3-hydroxykynurenine (HK), xanthurenic acid (XA), 3-hydroxyanthranilic acid (HAA), anthranilic acid (AA), picolinic acid (PA), and quinolinic acid (QA) were measured by liquid chromatography-tandem mass spectrometry. Using Cox proportional hazards regression, we examined associations of above-mentioned metabolites with all-cause mortality, adjusted for potential confounders. During a median follow-up of 3.2 years (interquartile range: 2.2-4.9), 290 patients (13.8%) deceased. Higher blood concentrations of tryptophan, XA, and PA were associated with a lower risk of all-cause mortality (per doubling in concentrations: tryptophan: HR = 0.56; 95%CI:0.41,0.76, XA: HR = 0.74; 95%CI:0.64,0.85, PA: HR = 0.76; 95%CI:0.64,0.92), while higher concentrations of HK and QA were associated with an increased risk of death (per doubling in concentrations: HK: HR = 1.80; 95%CI:1.47,2.21, QA: HR = 1.31; 95%CI:1.05,1.63). A higher kynurenine-to-tryptophan ratio, a marker of cell-mediated immune activation, was associated with an increased risk of death (per doubling: HR = 2.07; 95%CI:1.52,2.83). In conclusion, tryptophan-kynurenine pathway metabolites may be prognostic markers of survival in CRC patients.
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Affiliation(s)
- Victoria Damerell
- Department of General, Visceral and Transplantation SurgeryHeidelberg University HospitalHeidelbergGermany
| | - Niels Klaassen‐Dekker
- Division of Human Nutrition and HealthWageningen University & ResearchWageningenThe Netherlands
| | - Stefanie Brezina
- Center for Cancer ResearchMedical University of ViennaViennaAustria
| | - Jennifer Ose
- Huntsman Cancer InstituteSalt Lake CityUtahUSA
- Department of Population Health SciencesUniversity of UtahSalt Lake CityUtahUSA
- Department III: Media, Information and DesignUniversity of Applied Sciences and Arts, Hochschule HannoverHannoverGermany
| | | | - Eline H. van Roekel
- Department of Epidemiology, GROW School for Oncology and ReproductionMaastricht UniversityMaastrichtThe Netherlands
| | - Andreana N. Holowatyj
- Huntsman Cancer InstituteSalt Lake CityUtahUSA
- Department of Population Health SciencesUniversity of UtahSalt Lake CityUtahUSA
- Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Andreas Baierl
- Department of Statistics and Operations ResearchUniversity of ViennaViennaAustria
| | - Jürgen Böhm
- Huntsman Cancer InstituteSalt Lake CityUtahUSA
- Department of Population Health SciencesUniversity of UtahSalt Lake CityUtahUSA
| | - Martijn J. L. Bours
- Department of Epidemiology, GROW School for Oncology and ReproductionMaastricht UniversityMaastrichtThe Netherlands
| | - Hermann Brenner
- Division of Preventive OncologyNational Center for Tumor Diseases and German Cancer Research CenterHeidelbergGermany
- Division of Clinical Epidemiology and Aging ResearchGerman Cancer Research Center (DKFZ)HeidelbergGermany
- German Cancer Consortium (DKTK)German Cancer Research Center (DKFZ)HeidelbergGermany
| | - Johannes H. W. de Wilt
- Department of Surgery, Division of Surgical Oncology and Gastrointestinal SurgeryRadboud University Medical CenterNijmegenThe Netherlands
| | - William M. Grady
- Therapeutics and Translational Science DivisionFred Hutchinson Cancer Research CenterSeattleWashingtonUSA
| | - Nina Habermann
- Genome BiologyEuropean Molecular Biology Laboratory (EMBL)HeidelbergGermany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging ResearchGerman Cancer Research Center (DKFZ)HeidelbergGermany
| | - Pekka Keski‐Rahkonen
- Nutrition and Metabolism BranchInternational Agency for Research on CancerLyonFrance
| | - Tengda Lin
- Huntsman Cancer InstituteSalt Lake CityUtahUSA
- Department of Population Health SciencesUniversity of UtahSalt Lake CityUtahUSA
| | | | - Petra Schrotz‐King
- Division of Preventive OncologyNational Center for Tumor Diseases and German Cancer Research CenterHeidelbergGermany
| | - Alexis B. Ulrich
- Department of General, Visceral and Transplantation SurgeryHeidelberg University HospitalHeidelbergGermany
- Rheinland Klinikum NeussLukas KrankenhausNeussGermany
| | | | - Christy A. Warby
- Huntsman Cancer InstituteSalt Lake CityUtahUSA
- Department of Population Health SciencesUniversity of UtahSalt Lake CityUtahUSA
| | - David Shibata
- Department of SurgeryUniversity of Tennessee Health Science CenterMemphisTennesseeUSA
| | | | - Jane C. Figueiredo
- Department of Medicine, Samuel Oschin Comprehensive Cancer InstituteCedars‐Sinai Medical CenterCaliforniaLos AngelesUSA
| | - Erin M. Siegel
- Department of Cancer EpidemiologyH. Lee Moffitt Cancer Center and Research InstituteTampaFloridaUSA
| | - Christopher I. Li
- Division of Public Health SciencesFred Hutchinson Cancer CenterSeattleWashingtonUSA
| | - Andrea Gsur
- Center for Cancer ResearchMedical University of ViennaViennaAustria
| | - Ellen Kampman
- Division of Human Nutrition and HealthWageningen University & ResearchWageningenThe Netherlands
| | - Martin Schneider
- Department of General, Visceral and Transplantation SurgeryHeidelberg University HospitalHeidelbergGermany
| | | | - Matty P. Weijenberg
- Department of Epidemiology, GROW School for Oncology and ReproductionMaastricht UniversityMaastrichtThe Netherlands
| | - Cornelia M. Ulrich
- Huntsman Cancer InstituteSalt Lake CityUtahUSA
- Department of Population Health SciencesUniversity of UtahSalt Lake CityUtahUSA
| | - Dieuwertje E. Kok
- Division of Human Nutrition and HealthWageningen University & ResearchWageningenThe Netherlands
| | - Biljana Gigic
- Department of General, Visceral and Transplantation SurgeryHeidelberg University HospitalHeidelbergGermany
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Horozoglu C, Hakan MT, Sonmez D, Yildiz A, Demirkol S, Aktas F, Bagbudar S, Kucukhuseyin O, Arikan S, Akyuz F, Yaylim I. IDO1-mediated catabolism of tryptophan in gastric tumors: Its potential role in the axis of histopathology, differentiation and metastasis. Pathol Res Pract 2024; 263:155655. [PMID: 39442224 DOI: 10.1016/j.prp.2024.155655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 10/07/2024] [Accepted: 10/11/2024] [Indexed: 10/25/2024]
Abstract
BACKGROUND Indoleamine 2,3-Dioxygenase 1 (IDO1)-mediated tryptophan degradation, which is the rate-limiting enzyme of tryptophan/kynurenine pathway, may cause immune suppression in the tumor microenvironment, while potentiating proliferative and metastatic activity in the tumor focus, Phase studies of IDO1 inhibitors are ongoing, and our study aims to evaluate the potential contribution of IDO1 gene expression to the tryptophan/kynurenine pathway in tumor and tumor microenvironment foci in gastric cancer (GC) on a clinicopathological axis, METHOD: In the case-control study design, the determination of tryptophan and its metabolites in the serum of 51 GC and 49 healthy controls was made using High Pressure Liquid Chromatography-Fluorescence Detector (HPLC-FD). IDO1 expression in a total of 102 tissues with tumor and tumor microenvironment was detected by quantitative PCR (q-PCR). RESULTS In gastric tumors, 3,25-fold decreased expression of IDO1 was detected according to the tumor microenvironment (p=0,05), IDO1 expression was found to be more than 2 times higher in signet ring cell carcinoma (SRCC) and poorly differentiated tumors without distant organ metastasis (p<0,05), In GC, tryptophan level was found to be 1,6 times lower than in control (AUC:0889; cut off≤21,57; p<0001), Low tryptophan level was found in advanced tumor stage compared to early stage and in the presence of perineural invasion compared to its absence (p<0,05) The level of kynurenine was found to be approximately 1,8 times lower in SRCC (p=0,04), CONCLUSION: Increased tryptophan accumulation in the gastric tumor and its microenvironment, when catabolized via IDO1, exhibits histological type, tumor differentiation, and metastasis-promoting effects more prominently in aggressive subtypes such as SRCC.
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Affiliation(s)
- Cem Horozoglu
- Faculty of Medicine, Halic University, Istanbul, Turkey.
| | - Mehmet Tolgahan Hakan
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Dilara Sonmez
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Asli Yildiz
- Faculty of Medicine, Biruni University, Istanbul, Turkey
| | - Seyda Demirkol
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Fikret Aktas
- Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Sidar Bagbudar
- Department of Pathology, Basaksehir Cam and Sakura City Hospital, Istanbul, Turkey
| | - Ozlem Kucukhuseyin
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Soykan Arikan
- Department of General Surgery, Basaksehir Cam and Sakura City Hospital, Istanbul, Turkey
| | - Filiz Akyuz
- Department of Gastroenterohepatology, Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Ilhan Yaylim
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey.
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Alves LDF, Moore JB, Kell DB. The Biology and Biochemistry of Kynurenic Acid, a Potential Nutraceutical with Multiple Biological Effects. Int J Mol Sci 2024; 25:9082. [PMID: 39201768 PMCID: PMC11354673 DOI: 10.3390/ijms25169082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 08/16/2024] [Accepted: 08/19/2024] [Indexed: 09/03/2024] Open
Abstract
Kynurenic acid (KYNA) is an antioxidant degradation product of tryptophan that has been shown to have a variety of cytoprotective, neuroprotective and neuronal signalling properties. However, mammalian transporters and receptors display micromolar binding constants; these are consistent with its typically micromolar tissue concentrations but far above its serum/plasma concentration (normally tens of nanomolar), suggesting large gaps in our knowledge of its transport and mechanisms of action, in that the main influx transporters characterized to date are equilibrative, not concentrative. In addition, it is a substrate of a known anion efflux pump (ABCC4), whose in vivo activity is largely unknown. Exogeneous addition of L-tryptophan or L-kynurenine leads to the production of KYNA but also to that of many other co-metabolites (including some such as 3-hydroxy-L-kynurenine and quinolinic acid that may be toxic). With the exception of chestnut honey, KYNA exists at relatively low levels in natural foodstuffs. However, its bioavailability is reasonable, and as the terminal element of an irreversible reaction of most tryptophan degradation pathways, it might be added exogenously without disturbing upstream metabolism significantly. Many examples, which we review, show that it has valuable bioactivity. Given the above, we review its potential utility as a nutraceutical, finding it significantly worthy of further study and development.
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Affiliation(s)
- Luana de Fátima Alves
- The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Building 220, Søltofts Plads, 2800 Kongens Lyngby, Denmark
| | - J. Bernadette Moore
- School of Food Science & Nutrition, University of Leeds, Leeds LS2 9JT, UK;
- Department of Biochemistry, Cell & Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown St., Liverpool L69 7ZB, UK
| | - Douglas B. Kell
- The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Building 220, Søltofts Plads, 2800 Kongens Lyngby, Denmark
- Department of Biochemistry, Cell & Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown St., Liverpool L69 7ZB, UK
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Stone TW, Darlington LG, Badawy AAB, Williams RO. The Complex World of Kynurenic Acid: Reflections on Biological Issues and Therapeutic Strategy. Int J Mol Sci 2024; 25:9040. [PMID: 39201726 PMCID: PMC11354734 DOI: 10.3390/ijms25169040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 08/13/2024] [Accepted: 08/14/2024] [Indexed: 09/03/2024] Open
Abstract
It has been unequivocally established that kynurenic acid has a number of actions in a variety of cells and tissues, raising, in principle, the possibility of targeting its generation, metabolism or sites of action to manipulate those effects to a beneficial therapeutic end. However, many basic aspects of the biology of kynurenic acid remain unclear, potentially leading to some confusion and misinterpretations of data. They include questions of the source, generation, targets, enzyme expression, endogenous concentrations and sites of action. This essay is intended to raise and discuss many of these aspects as a source of reference for more balanced discussion. Those issues are followed by examples of situations in which modulating and correcting kynurenic acid production or activity could bring significant therapeutic benefit, including neurological and psychiatric conditions, inflammatory diseases and cell protection. More information is required to obtain a clear overall view of the pharmacological environment relevant to kynurenic acid, especially with respect to the active concentrations of kynurenine metabolites in vivo and changed levels in disease. The data and ideas presented here should permit a greater confidence in appreciating the sites of action and interaction of kynurenic acid under different local conditions and pathologies, enhancing our understanding of kynurenic acid itself and the many clinical conditions in which manipulating its pharmacology could be of clinical value.
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Affiliation(s)
- Trevor W. Stone
- The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford OX3 7FY, UK;
| | - L. Gail Darlington
- Worthing Hospital, University Hospitals Sussex NHS Foundation Trust, Worthing BN11 2DH, UK
| | - Abdulla A.-B. Badawy
- Formerly School of Health Sciences, Cardiff Metropolitan University, Cardiff CF5 2YB, UK
| | - Richard O. Williams
- The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford OX3 7FY, UK;
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Grishanova AY, Perepechaeva ML. Kynurenic Acid/AhR Signaling at the Junction of Inflammation and Cardiovascular Diseases. Int J Mol Sci 2024; 25:6933. [PMID: 39000041 PMCID: PMC11240928 DOI: 10.3390/ijms25136933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 06/14/2024] [Accepted: 06/21/2024] [Indexed: 07/14/2024] Open
Abstract
Persistent systemic chronic inflammatory conditions are linked with many pathologies, including cardiovascular diseases (CVDs), a leading cause of death across the globe. Among various risk factors, one of the new possible contributors to CVDs is the metabolism of essential amino acid tryptophan. Proinflammatory signals promote tryptophan metabolism via the kynurenine (KYN) pathway (KP), thereby resulting in the biosynthesis of several immunomodulatory metabolites whose biological effects are associated with the development of symptoms and progression of various inflammatory diseases. Some participants in the KP are agonists of aryl hydrocarbon receptor (AhR), a central player in a signaling pathway that, along with a regulatory influence on the metabolism of environmental xenobiotics, performs a key immunomodulatory function by triggering various cellular mechanisms with the participation of endogenous ligands to alleviate inflammation. An AhR ligand with moderate affinity is the central metabolite of the KP: KYN; one of the subsequent metabolites of KYN-kynurenic acid (KYNA)-is a more potent ligand of AhR. Understanding the role of AhR pathway-related metabolites of the KP that regulate inflammatory factors in cells of the cardiovascular system is interesting and important for achieving effective treatment of CVDs. The purpose of this review was to summarize the results of studies about the participation of the KP metabolite-KYNA-and of the AhR signaling pathway in the regulation of inflammation in pathological conditions of the heart and blood vessels and about the possible interaction of KYNA with AhR signaling in some CVDs.
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Affiliation(s)
| | - Maria L. Perepechaeva
- Institute of Molecular Biology and Biophysics, Federal Research Center of Fundamental and Translational Medicine, Timakova Str. 2, Novosibirsk 630060, Russia;
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Yu L, Lu J, Du W. Tryptophan metabolism in digestive system tumors: unraveling the pathways and implications. Cell Commun Signal 2024; 22:174. [PMID: 38462620 PMCID: PMC10926624 DOI: 10.1186/s12964-024-01552-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Accepted: 03/01/2024] [Indexed: 03/12/2024] Open
Abstract
Tryptophan (Trp) metabolism plays a crucial role in influencing the development of digestive system tumors. Dysregulation of Trp and its metabolites has been identified in various digestive system cancers, including esophageal, gastric, liver, colorectal, and pancreatic cancers. Aberrantly expressed Trp metabolites are associated with diverse clinical features in digestive system tumors. Moreover, the levels of these metabolites can serve as prognostic indicators and predictors of recurrence risk in patients with digestive system tumors. Trp metabolites exert their influence on tumor growth and metastasis through multiple mechanisms, including immune evasion, angiogenesis promotion, and drug resistance enhancement. Suppressing the expression of key enzymes in Trp metabolism can reduce the accumulation of these metabolites, effectively impacting their role in the promotion of tumor progression and metastasis. Strategies targeting Trp metabolism through specific enzyme inhibitors or tailored drugs exhibit considerable promise in enhancing therapeutic outcomes for digestive system tumors. In addition, integrating these approaches with immunotherapy holds the potential to further enhance treatment efficacy.
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Affiliation(s)
- Liang Yu
- State Key Laboratory for Diagnosis, Treatment of Infectious Diseases,, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, 310003, China
| | - Juan Lu
- State Key Laboratory for Diagnosis, Treatment of Infectious Diseases,, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, 310003, China.
| | - Weibo Du
- State Key Laboratory for Diagnosis, Treatment of Infectious Diseases,, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, 310003, China.
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Gawel K. A Review on the Role and Function of Cinnabarinic Acid, a "Forgotten" Metabolite of the Kynurenine Pathway. Cells 2024; 13:453. [PMID: 38474418 PMCID: PMC10930587 DOI: 10.3390/cells13050453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 03/01/2024] [Accepted: 03/02/2024] [Indexed: 03/14/2024] Open
Abstract
In the human body, the majority of tryptophan is metabolized through the kynurenine pathway. This consists of several metabolites collectively called the kynurenines and includes, among others, kynurenic acid, L-kynurenine, or quinolinic acid. The wealth of metabolites, as well as the associated molecular targets and biological pathways, bring about a situation wherein even a slight imbalance in the kynurenine levels, both in the periphery and central nervous system, have broad consequences regarding general health. Cinnabarinic acid (CA) is the least known trace kynurenine, and its physiological and pathological roles are not widely understood. Some studies, however, indicate that it might be neuroprotective. Information on its hepatoprotective properties have also emerged, although these are pioneering studies and need to be replicated. Therefore, in this review, I aim to present and critically discuss the current knowledge on CA and its role in physiological and pathological settings to guide future studies.
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Affiliation(s)
- Kinga Gawel
- Department of Experimental and Clinical Pharmacology, Medical University of Lublin, Jaczewskiego 8b Str., 20-090 Lublin, Poland
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10
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Nazeam JA, Boshra SA, Mohammed EZ, El Gizawy HA. Bio-Guided Assay of Ephedra foeminea Forssk Extracts and Anticancer Activities: In Vivo, In Vitro, and In Silico Evaluations. Molecules 2023; 29:199. [PMID: 38202783 PMCID: PMC10780881 DOI: 10.3390/molecules29010199] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/17/2023] [Accepted: 12/21/2023] [Indexed: 01/12/2024] Open
Abstract
Ephedra is one of the oldest known medicinal plants and the largest genera of the Ephedraceae family. In vivo antitumor evaluation of Ephedra foeminea revealed that ethyl acetate (EtOAc) was the most bioactive fraction. Bio-guided fractionation of EtOAc fraction afforded nine compounds isolated for the first time from the plant species. Macrocyclic spermine alkaloids (1,9), proanthocyanidins (2,4,5), quinoline alkaloids (7,8), phenolic (3), and nucleoside (6) were identified and elucidated by spectroscopic analyses including 1D and 2D NMR, ESI-MS-MS spectrometry. The tested compounds exhibited moderate anticancer activity, except for the kynurenic acid derivative (6-mKYNA) which showed significant cytotoxicity and remarkable inhibition of CA-19.9 and CA-125 tumor biomarkers. In-silico study was conducted to determine the anti-proliferative mechanism of 6-mKYNA by using the CK2 enzyme active site. Moreover, the ADME computational study suggested that 6-mKYNA is an effective candidate with a promising pharmacokinetic profile and therapeutic potential against various types of cancer.
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Affiliation(s)
- Jilan A. Nazeam
- Pharmacognosy Department, Faculty of Pharmacy, October 6 University, 6th of October City 12585, Egypt;
| | - Sylvia A. Boshra
- Biochemistry Department, Faculty of Pharmacy, October 6 University, 6th of October City 12585, Egypt;
| | - Esraa Z. Mohammed
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, October 6 University, 6th of October City 12585, Egypt;
| | - Heba A. El Gizawy
- Pharmacognosy Department, Faculty of Pharmacy, October 6 University, 6th of October City 12585, Egypt;
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11
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Hou Y, Li J, Ying S. Tryptophan Metabolism and Gut Microbiota: A Novel Regulatory Axis Integrating the Microbiome, Immunity, and Cancer. Metabolites 2023; 13:1166. [PMID: 37999261 PMCID: PMC10673612 DOI: 10.3390/metabo13111166] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 11/16/2023] [Accepted: 11/18/2023] [Indexed: 11/25/2023] Open
Abstract
Tryptophan metabolism and gut microbiota form an integrated regulatory axis that impacts immunity, metabolism, and cancer. This review consolidated current knowledge on the bidirectional interactions between microbial tryptophan processing and the host. We focused on how the gut microbiome controls tryptophan breakdown via the indole, kynurenine, and serotonin pathways. Dysbiosis of the gut microbiota induces disruptions in tryptophan catabolism which contribute to disorders like inflammatory conditions, neuropsychiatric diseases, metabolic syndromes, and cancer. These disruptions affect immune homeostasis, neurotransmission, and gut-brain communication. Elucidating the mechanisms of microbial tryptophan modulation could enable novel therapeutic approaches like psychobiotics and microbiome-targeted dietary interventions. Overall, further research on the microbiota-tryptophan axis has the potential to revolutionize personalized diagnostics and treatments for improving human health.
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Affiliation(s)
- Yingjian Hou
- Target Discovery Center, China Pharmaceutical University, Nanjing 211198, China;
| | - Jing Li
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
- Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha 410000, China
| | - Shuhuan Ying
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
- Shanghai Bocimed Pharmaceutical Research Co., Ltd., Shanghai 201203, China
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12
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Sadok I, Jędruchniewicz K. Dietary Kynurenine Pathway Metabolites-Source, Fate, and Chromatographic Determinations. Int J Mol Sci 2023; 24:16304. [PMID: 38003492 PMCID: PMC10671297 DOI: 10.3390/ijms242216304] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 11/10/2023] [Accepted: 11/12/2023] [Indexed: 11/26/2023] Open
Abstract
Tryptophan metabolism plays an essential role in human health. In mammals, about 95% of dietary tryptophan is metabolized through the kynurenine pathway, which is associated with the development of several pathologies, including neurodegeneration. Some of the kynurenine pathway metabolites are agonists of the aryl hydrocarbon receptor involved in metabolic functions, inflammation, and carcinogenesis. Thus, their origins, fates, and roles are of widespread interest. Except for being produced endogenously, these metabolites can originate from exogenous sources (e.g., food) and undergo absorption in the digestive tract. Recently, a special focus on exogenous sources of tryptophan metabolites was observed. This overview summarizes current knowledge about the occurrence of the kynurenine pathway metabolites (kynurenines) in food and the analytical method utilized for their determination in different food matrices. Special attention was paid to sample preparation and chromatographic analysis, which has proven to be a core technique for the detection and quantification of kynurenines. A discussion of the fate and role of dietary kynurenines has also been addressed. This review will, hopefully, guide further studies on the impact of dietary kynurenines on human health.
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Affiliation(s)
- Ilona Sadok
- Laboratory of Separation and Spectroscopic Method Applications, Department of Chemistry, Institute of Biological Sciences, Faculty of Medicine, The John Paul II Catholic University of Lublin, 20-708 Lublin, Poland
| | - Katarzyna Jędruchniewicz
- Laboratory of Separation and Spectroscopic Method Applications, The John Paul II Catholic University of Lublin, 20-708 Lublin, Poland;
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13
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Basson C, Serem JC, Hlophe YN, Bipath P. An in vitro investigation of l-kynurenine, quinolinic acid, and kynurenic acid on B16 F10 melanoma cell cytotoxicity and morphology. Cell Biochem Funct 2023; 41:912-922. [PMID: 37661337 DOI: 10.1002/cbf.3843] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 08/03/2023] [Accepted: 08/20/2023] [Indexed: 09/05/2023]
Abstract
The metastatic behavior of melanoma has accentuated the need for specific therapy targets. Compounds, namely l-kynurenine ( l-kyn), quinolinic acid (Quin), and kynurenic acid (KA) previously displayed antiproliferative and cytotoxic effects in vitro against cancer cells. Despite the growing interest in these compounds there are limited studies examining the in vitro effects on melanoma. In B16 F10 melanoma cells, RAW 264.7 macrophage cells, and HaCat keratinocyte cells, postexposure to the compounds, crystal violet staining was used to determine the half-maximal inhibitory concentration (IC50 ), whereas polarization-optical transmitted light differential interference contrast and light microscopy after hematoxylin and eosin (H&E) staining was used to assess morphological changes. l-kyn, Quin, and KA-induced cytotoxicity in all cell lines, with l-kyn being the most cytotoxic compound. l-kyn and KA at IC50 -induced morphological changes in B16 F10, RAW 264.7, and HaCat cell lines, whereas Quin had effects on B16 F10 and RAW 264.7 cells but did not affect HaCat cells. l-kyn, Quin, and KA each display different levels of cytotoxicity, which were cell line specific. l-kyn was shown to be the most potent compound against all cell lines and may offer future treatment strategies when combined with other viable treatments against melanoma.
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Affiliation(s)
- Charlise Basson
- Department of Physiology, School of Medicine, University of Pretoria, Pretoria, South Africa
| | - June Cheptoo Serem
- Department of Anatomy, School of Medicine, University of Pretoria, Pretoria, South Africa
| | - Yvette Nkondo Hlophe
- Department of Physiology, School of Medicine, University of Pretoria, Pretoria, South Africa
| | - Priyesh Bipath
- Department of Physiology, School of Medicine, University of Pretoria, Pretoria, South Africa
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14
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Ziuzia P, Janiec Z, Wróbel-Kwiatkowska M, Lazar Z, Rakicka-Pustułka M. Honey's Yeast-New Source of Valuable Species for Industrial Applications. Int J Mol Sci 2023; 24:ijms24097889. [PMID: 37175595 PMCID: PMC10178026 DOI: 10.3390/ijms24097889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 04/21/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023] Open
Abstract
Honey is a rich source of compounds with biological activity; moreover, it is a valuable source of various microorganisms. The aim of this study was to isolate and identify yeast from a sample of lime honey from Poland as well as to assess its ability to biosynthesize value-added chemicals such as kynurenic acid, erythritol, mannitol, and citric acid on common carbon sources. Fifteen yeast strains belonging to the species Yarrowia lipolytica, Candida magnolia, and Starmerella magnoliae were isolated. In shake-flask screening, the best value-added compound producers were chosen. In the last step, scaling up of the culture in the bioreactor was performed. A newly isolated strain of Y. lipolytica No. 12 produced 3.9 mg/L of kynurenic acid growing on fructose. Strain Y. lipolytica No. 9 synthesized 32.6 g/L of erythritol on technical glycerol with a low concentration of byproducts. Strain Y. lipolytica No. 5 produced 15.1 g/L of mannitol on technical glycerol, and strain No. 3 produced a very high amount of citric acid (76.6 g/L) on technical glycerol. In conclusion, to the best of our knowledge this is the first study to report the use of yeast isolates from honey to produce valuable chemicals. This study proves that natural products such as lime honey can be an excellent source of wild-type yeasts with valuable production properties.
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Affiliation(s)
- Patrycja Ziuzia
- Department of Biochemistry and Molecular Biology, Wroclaw University of Environmental and Life Sciences, 31 Norwida St., 50-375 Wroclaw, Poland
| | - Zuzanna Janiec
- Department of Biotechnology and Food Microbiology, Wroclaw University of Environmental and Life Sciences, 37 Chełmońskiego St., 51-630 Wroclaw, Poland
| | - Magdalena Wróbel-Kwiatkowska
- Department of Biotechnology and Food Microbiology, Wroclaw University of Environmental and Life Sciences, 37 Chełmońskiego St., 51-630 Wroclaw, Poland
| | - Zbigniew Lazar
- Department of Biotechnology and Food Microbiology, Wroclaw University of Environmental and Life Sciences, 37 Chełmońskiego St., 51-630 Wroclaw, Poland
| | - Magdalena Rakicka-Pustułka
- Department of Biotechnology and Food Microbiology, Wroclaw University of Environmental and Life Sciences, 37 Chełmońskiego St., 51-630 Wroclaw, Poland
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15
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PPARs and the Kynurenine Pathway in Melanoma-Potential Biological Interactions. Int J Mol Sci 2023; 24:ijms24043114. [PMID: 36834531 PMCID: PMC9960262 DOI: 10.3390/ijms24043114] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/28/2023] [Accepted: 02/01/2023] [Indexed: 02/08/2023] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors involved in various physiological and pathological processes within the skin. PPARs regulate several processes in one of the most aggressive skin cancers, melanoma, including proliferation, cell cycle, metabolic homeostasis, cell death, and metastasis. In this review, we focused not only on the biological activity of PPAR isoforms in melanoma initiation, progression, and metastasis but also on potential biological interactions between the PPAR signaling and the kynurenine pathways. The kynurenine pathway is a major pathway of tryptophan metabolism leading to nicotinamide adenine dinucleotide (NAD+) production. Importantly, various tryptophan metabolites exert biological activity toward cancer cells, including melanoma. Previous studies confirmed the functional relationship between PPAR and the kynurenine pathway in skeletal muscles. Despite the fact this interaction has not been reported in melanoma to date, some bioinformatics data and biological activity of PPAR ligands and tryptophan metabolites may suggest a potential involvement of these metabolic and signaling pathways in melanoma initiation, progression, and metastasis. Importantly, the possible relationship between the PPAR signaling pathway and the kynurenine pathway may relate not only to the direct biological effect on melanoma cells but also to the tumor microenvironment and the immune system.
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16
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Turska M, Paluszkiewicz P, Turski WA, Parada-Turska J. A Review of the Health Benefits of Food Enriched with Kynurenic Acid. Nutrients 2022; 14:4182. [PMID: 36235834 PMCID: PMC9570704 DOI: 10.3390/nu14194182] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 10/02/2022] [Accepted: 10/04/2022] [Indexed: 11/17/2022] Open
Abstract
Kynurenic acid (KYNA), a metabolite of tryptophan, is an endogenous substance produced intracellularly by various human cells. In addition, KYNA can be synthesized by the gut microbiome and delivered in food. However, its content in food is very low and the total alimentary supply with food accounts for only 1-3% of daily KYNA excretion. The only known exception is chestnut honey, which has a higher KYNA content than other foods by at least two orders of magnitude. KYNA is readily absorbed from the gastrointestinal tract; it is not metabolized and is excreted mainly in urine. It possesses well-defined molecular targets, which allows the study and elucidation of KYNA's role in various pathological conditions. Following a period of fascination with KYNA's importance for the central nervous system, research into its role in the peripheral system has been expanding rapidly in recent years, bringing some exciting discoveries. KYNA does not penetrate from the peripheral circulation into the brain; hence, the following review summarizes knowledge on the peripheral consequences of KYNA administration, presents data on KYNA content in food products, in the context of its daily supply in diets, and systematizes the available pharmacokinetic data. Finally, it provides an analysis of the rationale behind enriching foods with KYNA for health-promoting effects.
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Affiliation(s)
- Monika Turska
- Department of Molecular Biology, The John Paul II Catholic University of Lublin, 20-708 Lublin, Poland
| | - Piotr Paluszkiewicz
- Department of General, Oncological and Metabolic Surgery, Institute of Hematology and Transfusion Medicine, 02-778 Warsaw, Poland
| | - Waldemar A. Turski
- Department of Experimental and Clinical Pharmacology, Medical University of Lublin, 20-090 Lublin, Poland
| | - Jolanta Parada-Turska
- Department of Rheumatology and Connective Tissue Diseases, Medical University of Lublin, 20-090 Lublin, Poland
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17
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Moritsch S, Mödl B, Scharf I, Janker L, Zwolanek D, Timelthaler G, Casanova E, Sibilia M, Mohr T, Kenner L, Herndler-Brandstetter D, Gerner C, Müller M, Strobl B, Eferl R. Tyk2 is a tumor suppressor in colorectal cancer. Oncoimmunology 2022; 11:2127271. [PMID: 36185806 PMCID: PMC9519006 DOI: 10.1080/2162402x.2022.2127271] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 09/15/2022] [Accepted: 09/15/2022] [Indexed: 12/04/2022] Open
Abstract
Janus kinase Tyk2 is implicated in cancer immune surveillance, but its role in solid tumors is not well defined. We used Tyk2 knockout mice (Tyk2Δ/Δ) and mice with conditional deletion of Tyk2 in hematopoietic (Tyk2ΔHem) or intestinal epithelial cells (Tyk2ΔIEC) to assess their cell type-specific functions in chemically induced colorectal cancer. All Tyk2-deficient mouse models showed a higher tumor burden after AOM-DSS treatment compared to their corresponding wild-type controls (Tyk2+/+ and Tyk2fl/fl), demonstrating tumor-suppressive functions of Tyk2 in immune cells and epithelial cancer cells. However, specific deletion of Tyk2 in hematopoietic cells or in intestinal epithelial cells was insufficient to accelerate tumor progression, while deletion in both compartments promoted carcinoma formation. RNA-seq and proteomics revealed that tumors of Tyk2Δ/Δ and Tyk2ΔIEC mice were immunoedited in different ways with downregulated and upregulated IFNγ signatures, respectively. Accordingly, the IFNγ-regulated immune checkpoint Ido1 was downregulated in Tyk2Δ/Δ and upregulated in Tyk2ΔIEC tumors, although both showed reduced CD8+ T cell infiltration. These data suggest that Tyk2Δ/Δ tumors are Ido1-independent and poorly immunoedited while Tyk2ΔIEC tumors require Ido1 for immune evasion. Our study shows that Tyk2 prevents Ido1 expression in CRC cells and promotes CRC immune surveillance in the tumor stroma. Both of these Tyk2-dependent mechanisms must work together to prevent CRC progression.
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Affiliation(s)
- Stefan Moritsch
- Center for Cancer Research, Medical University of Vienna & Comprehensive Cancer Center, Vienna, Austria
| | - Bernadette Mödl
- Center for Cancer Research, Medical University of Vienna & Comprehensive Cancer Center, Vienna, Austria
| | - Irene Scharf
- Center for Cancer Research, Medical University of Vienna & Comprehensive Cancer Center, Vienna, Austria
| | - Lukas Janker
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria
- Joint Metabolomics Facility, University and Medical University of Vienna, Vienna, Austria
| | - Daniela Zwolanek
- Center for Cancer Research, Medical University of Vienna & Comprehensive Cancer Center, Vienna, Austria
| | - Gerald Timelthaler
- Center for Cancer Research, Medical University of Vienna & Comprehensive Cancer Center, Vienna, Austria
| | - Emilio Casanova
- Department of Pharmacology, Center of Physiology and Pharmacology & Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Maria Sibilia
- Center for Cancer Research, Medical University of Vienna & Comprehensive Cancer Center, Vienna, Austria
| | - Thomas Mohr
- Center for Cancer Research, Medical University of Vienna & Comprehensive Cancer Center, Vienna, Austria
| | - Lukas Kenner
- Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria
| | | | - Christopher Gerner
- Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria
- Joint Metabolomics Facility, University and Medical University of Vienna, Vienna, Austria
| | - Mathias Müller
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Birgit Strobl
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Robert Eferl
- Center for Cancer Research, Medical University of Vienna & Comprehensive Cancer Center, Vienna, Austria
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18
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Mazzini S, Princiotto S, Musso L, Passarella D, Beretta GL, Perego P, Dallavalle S. Synthesis and Investigation of the G-Quadruplex Binding Properties of Kynurenic Acid Derivatives with a Dihydroimidazoquinoline-3,5-dione Core. Molecules 2022; 27:2791. [PMID: 35566141 PMCID: PMC9103425 DOI: 10.3390/molecules27092791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 04/21/2022] [Accepted: 04/25/2022] [Indexed: 11/16/2022] Open
Abstract
G-quadruplexes are secondary structures originating from nucleic acid regions rich in guanines, which are well known for their involvement in gene transcription and regulation and DNA damage repair. In recent studies from our group, kynurenic acid (KYNA) derivative 1 was synthesized and found to share the structural features typical of G-quadruplex binders. Herein, structural modifications were conducted on this scaffold in order to assist the binding with a G-quadruplex, by introducing charged hydrophilic groups. The antiproliferative activity of the new analogues was evaluated on an IGROV-1 human ovarian cancer cell line, and the most active compound, compound 9, was analyzed with NMR spectrometry in order to investigate its binding mode with DNA. The results indicated that a weak, non-specific interaction was set with duplex nucleotides; on the other hand, titration in the presence of a G-quadruplex from human telomere d(TTAGGGT)4 showed a stable, although not strong, interaction at the 3'-end of the nucleotidic sequence, efficiently assisted by salt bridges between the quaternary nitrogen and the external phosphate groups. Overall, this work can be considered a platform for the development of a new class of potential G-quadruplex stabilizing molecules, confirming the crucial role of a planar system and the ability of charged nitrogen-containing groups to facilitate the binding to G-quadruplex grooves and loops.
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Affiliation(s)
- Stefania Mazzini
- Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, Via Celoria 2, 20133 Milan, Italy; (S.M.); (L.M.); (S.D.)
| | - Salvatore Princiotto
- Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, Via Celoria 2, 20133 Milan, Italy; (S.M.); (L.M.); (S.D.)
| | - Loana Musso
- Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, Via Celoria 2, 20133 Milan, Italy; (S.M.); (L.M.); (S.D.)
| | | | - Giovanni Luca Beretta
- Molecular Pharmacology Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, 20133 Milan, Italy; (G.L.B.); (P.P.)
| | - Paola Perego
- Molecular Pharmacology Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, 20133 Milan, Italy; (G.L.B.); (P.P.)
| | - Sabrina Dallavalle
- Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, Via Celoria 2, 20133 Milan, Italy; (S.M.); (L.M.); (S.D.)
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19
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Emerging effects of tryptophan pathway metabolites and intestinal microbiota on metabolism and intestinal function. Amino Acids 2022; 54:57-70. [PMID: 35038025 DOI: 10.1007/s00726-022-03123-x] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 01/03/2022] [Indexed: 12/14/2022]
Abstract
The metabolism of dietary tryptophan occurs locally in the gut primarily via host enzymes, with ~ 5% metabolized by gut microbes. Three major tryptophan metabolic pathways are serotonin (beyond the scope of this review), indole, kynurenine and related derivatives. We introduce the gut microbiome, dietary tryptophan and the potential interplay of host and bacterial enzymes in tryptophan metabolism. Examples of bacterial transformation to indole and its derivative indole-3 propionic acid demonstrate associations with human metabolic disease and gut permeability, although causality remains to be determined. This review will focus on less well-known data, suggestive of local generation and functional significance in the gut, where kynurenine is converted to kynurenic acid and xanthurenic acid via enzymatic action present in both host and bacteria. Our functional data demonstrate a limited effect on intestinal epithelial cell monolayer permeability and on healthy mouse ileum. Other data suggest a modulatory effect on the microbiome, potentially in pathophysiology. Supportive of this, we found that the expression of mRNA for three kynurenine pathway enzymes were increased in colon from high-fat-fed mice, suggesting that this host pathway is perturbed in metabolic disease. These data, along with that from bacterial genomic analysis and germ-free mice, confirms expression and functional machinery of enzymes in this pathway. Therefore, the host and microbiota may play a significant dual role in either the production or regulation of these kynurenine metabolites which, in turn, can influence both host and microbiome, especially in the context of obesity and intestinal permeability.
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20
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Haq S, Grondin JA, Khan WI. Tryptophan-derived serotonin-kynurenine balance in immune activation and intestinal inflammation. FASEB J 2021; 35:e21888. [PMID: 34473368 PMCID: PMC9292703 DOI: 10.1096/fj.202100702r] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 07/29/2021] [Accepted: 08/16/2021] [Indexed: 02/06/2023]
Abstract
Endogenous tryptophan metabolism pathways lead to the production of serotonin (5‐hydroxytryptamine; 5‐HT), kynurenine, and several downstream metabolites which are involved in a multitude of immunological functions in both health and disease states. Ingested tryptophan is largely shunted to the kynurenine pathway (95%) while only minor portions (1%–2%) are sequestered for 5‐HT production. Though often associated with the functioning of the central nervous system, significant production of 5‐HT, kynurenine and their downstream metabolites takes place within the gut. Accumulating evidence suggests that these metabolites have essential roles in regulating immune cell function, intestinal inflammation, as well as in altering the production and suppression of inflammatory cytokines. In addition, both 5‐HT and kynurenine have a considerable influence on gut microbiota suggesting that these metabolites impact host physiology both directly and indirectly via compositional changes. It is also now evident that complex interactions exist between the two pathways to maintain gut homeostasis. Alterations in 5‐HT and kynurenine are implicated in the pathogenesis of many gastrointestinal dysfunctions, including inflammatory bowel disease. Thus, these pathways present numerous potential therapeutic targets, manipulation of which may aid those suffering from gastrointestinal disorders. This review aims to update both the role of 5‐HT and kynurenine in immune regulation and intestinal inflammation, and analyze the current knowledge of the relationship and interactions between 5‐HT and kynurenine pathways.
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Affiliation(s)
- Sabah Haq
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Jensine A Grondin
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Waliul I Khan
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.,Laboratory Medicine, Hamilton Health Sciences, Hamilton, Ontario, Canada
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21
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Ala M. Tryptophan metabolites modulate inflammatory bowel disease and colorectal cancer by affecting immune system. Int Rev Immunol 2021; 41:326-345. [PMID: 34289794 DOI: 10.1080/08830185.2021.1954638] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Tryptophan is an essential amino acid, going through three different metabolic pathways in the intestines. Indole pathway in the gut microbiota, serotonin system in the enterochromaffin cells and kynurenine pathway in the immune cells and intestinal lining are the three arms of tryptophan metabolism in the intestines. Clinical, in vivo and in vitro studies showed that each one of these arms has a significant impact on IBD. This review explains how different metabolites of tryptophan are involved in the pathophysiology of IBD and colorectal cancer, as a major complication of IBD. Indole metabolites alleviate colitis and protect against colorectal cancer while serotonin arm follows a more complicated and receptor-specific pattern. Indole metabolites and kynurenine interact with aryl hydrocarbon receptor (AHR) to induce T regulatory cells differentiation, confine Th17 and Th1 response and produce anti-inflammatory mediators. Kynurenine decreases tumor-infiltrating CD8+ cells and mediates tumor cells immune evasion. Serotonin system also increases colorectal cancer cells proliferation and metastasis while, indole metabolites can profoundly decrease colorectal cancer growth. Targeted therapy for tryptophan metabolites may improve the management of IBD and colorectal cancer, e.g. supplementation of indole metabolites such as indole-3-carbinol (I3C), inhibition of kynurenine monooxygenase (KMO) and selective stimulation or inhibition of specific serotonergic receptors can mitigate colitis. Furthermore, it will be explained how indole metabolites supplementation, inhibition of indoleamine 2,3-dioxygenase 1 (IDO1), KMO and serotonin receptors can protect against colorectal cancer. Additionally, extensive molecular interactions between tryptophan metabolites and intracellular signaling pathways will be thoroughly discussed.
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Affiliation(s)
- Moein Ala
- School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
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22
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Walczak K, Kazimierczak P, Szalast K, Plech T. UVB Radiation and Selected Tryptophan-Derived AhR Ligands-Potential Biological Interactions in Melanoma Cells. Int J Mol Sci 2021; 22:ijms22147500. [PMID: 34299117 PMCID: PMC8307169 DOI: 10.3390/ijms22147500] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 07/08/2021] [Accepted: 07/10/2021] [Indexed: 12/12/2022] Open
Abstract
Excessive UV exposure is considered the major environmental factor in melanoma progression. Human skin is constantly exposed to selected tryptophan-derived aryl hydrocarbon receptor (AhR) ligands, including kynurenine (KYN) and kynurenic acid (KYNA), as they are endogenously produced and present in various tissues and body fluids. Importantly, recent studies confirmed the biological activity of KYN and KYNA toward melanoma cells in vitro. Thus, in this study, the potential biological interactions between UVB and tryptophan metabolites KYN and KYNA were studied in melanoma A375, SK-MEL-3, and RPMI-7951 cells. It was shown that UVB enhanced the antiproliferative activity of KYN and KYNA in melanoma cells. Importantly, selected tryptophan-derived AhR ligands did not affect the invasiveness of A375 and RPMI-7951 cells; however, the stimulatory effect was observed in SK-MEL-3 cells exposed to UVB. Thus, the effect of tryptophan metabolites on metabolic activity, cell cycle regulation, and cell death in SK-MEL-3 cells exposed to UVB was assessed. In conclusion, taking into account that both UVB radiation and tryptophan-derived AhR ligands may have a crucial effect on skin cancer formation and progression, these results may have a significant impact, revealing the potential biological interactions in melanoma cells in vitro.
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Affiliation(s)
- Katarzyna Walczak
- Department of Pharmacology, Medical University of Lublin, Chodźki 4a, 20093 Lublin, Poland; (K.S.); (T.P.)
- Correspondence: ; Tel.: +48-814-486-774
| | - Paulina Kazimierczak
- Department of Biochemistry and Biotechnology, Medical University of Lublin, Chodźki 1, 20093 Lublin, Poland;
| | - Karolina Szalast
- Department of Pharmacology, Medical University of Lublin, Chodźki 4a, 20093 Lublin, Poland; (K.S.); (T.P.)
| | - Tomasz Plech
- Department of Pharmacology, Medical University of Lublin, Chodźki 4a, 20093 Lublin, Poland; (K.S.); (T.P.)
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23
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Selvam AK, Jawad R, Gramignoli R, Achour A, Salter H, Björnstedt M. A Novel mRNA-Mediated and MicroRNA-Guided Approach to Specifically Eradicate Drug-Resistant Hepatocellular Carcinoma Cell Lines by Se-Methylselenocysteine. Antioxidants (Basel) 2021; 10:1094. [PMID: 34356326 PMCID: PMC8301172 DOI: 10.3390/antiox10071094] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/28/2021] [Accepted: 07/01/2021] [Indexed: 01/25/2023] Open
Abstract
Despite progress in the treatment of non-visceral malignancies, the prognosis remains poor for malignancies of visceral organs and novel therapeutic approaches are urgently required. We evaluated a novel therapeutic regimen based on treatment with Se-methylselenocysteine (MSC) and concomitant tumor-specific induction of Kynurenine aminotransferase 1 (KYAT1) in hepatocellular carcinoma (HCC) cell lines, using either vector-based and/or lipid nanoparticle-mediated delivery of mRNA. Supplementation of MSC in KYAT1 overexpressed cells resulted in significantly increased cytotoxicity, due to ROS formation, as compared to MSC alone. Furthermore, microRNA antisense-targeted sites for miR122, known to be widely expressed in normal hepatocytes while downregulated in hepatocellular carcinoma, were added to specifically limit cytotoxicity in HCC cells, thereby limiting the off-target effects. KYAT1 expression was significantly reduced in cells with high levels of miR122 supporting the concept of miR-guided induction of tumor-specific cytotoxicity. The addition of alpha-ketoacid favored the production of methylselenol, enhancing the cytotoxic efficacy of MSC in HCC cells, with no effects on primary human hepatocytes. Altogether, the proposed regimen offers great potential to safely and specifically target hepatic tumors that are currently untreatable.
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Affiliation(s)
- Arun Kumar Selvam
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Karolinska University Hospital, S-141 86 Stockholm, Sweden; (A.K.S.); (R.J.); (R.G.); (H.S.)
| | - Rim Jawad
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Karolinska University Hospital, S-141 86 Stockholm, Sweden; (A.K.S.); (R.J.); (R.G.); (H.S.)
| | - Roberto Gramignoli
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Karolinska University Hospital, S-141 86 Stockholm, Sweden; (A.K.S.); (R.J.); (R.G.); (H.S.)
| | - Adnane Achour
- Science for Life Laboratory, Department of Medicine Solna, Karolinska Institute, & Division of Infectious Diseases, Karolinska University Hospital, SE-171 77 Solna, Sweden;
| | - Hugh Salter
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Karolinska University Hospital, S-141 86 Stockholm, Sweden; (A.K.S.); (R.J.); (R.G.); (H.S.)
- Moderna, Inc., 200 Technology Square, Cambridge, MA 02139, USA
| | - Mikael Björnstedt
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Karolinska University Hospital, S-141 86 Stockholm, Sweden; (A.K.S.); (R.J.); (R.G.); (H.S.)
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24
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Lin J, Sun-Waterhouse D, Cui C. The therapeutic potential of diet on immune-related diseases: based on the regulation on tryptophan metabolism. Crit Rev Food Sci Nutr 2021; 62:8793-8811. [PMID: 34085885 DOI: 10.1080/10408398.2021.1934813] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Tryptophan (TRP), as an essential amino acid, plays crucial roles in maintaining immune homeostasis due to its complex metabolism pathway, including the microbial metabolism, 5-hydroxytryptamine and kynurenine pathways (KP). Metabolites from these pathways can act antioxidant and endogenous ligand of aryl hydrocarbon receptor (including microbiota metabolites: indole, indole aldehyde, indole acetic acid, indole acrylic acid, indole lactate, indole pyruvate acid, indole propionic acid, skatole, tryptamine, and indoxyl sulfate; and KP metabolites: kynurenine, kynurenic acid, 3-hydroxyanthranilic acid, xanthurenic acid, and cinnabarinic acid) for regulating immune response. In immune-related diseases, the production of pro-inflammatory cytokine activates indoleamine-2,3-dioxygenase, a rate-limiting enzyme of KP, leading to abnormal TRP metabolism in vivo. Many recent studies found that TRP metabolism could be regulated by diet, and the diet regulation on TRP metabolism could therapy related diseases. Accordingly, this review provides a critical overview of the relationships among diet, TRP metabolism and immunity with the aim to seek a treatment opportunity for immune-related diseases.
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Affiliation(s)
- Junjie Lin
- College of Food Science and Technology, South China University of Technology, Guangzhou, China
| | - Dongxiao Sun-Waterhouse
- College of Food Science and Technology, South China University of Technology, Guangzhou, China
| | - Chun Cui
- College of Food Science and Technology, South China University of Technology, Guangzhou, China.,Guangdong Wei-Wei Biotechnology Co., Ltd, Guangzhou, China
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25
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Sun XZ, Zhao DY, Zhou YC, Wang QQ, Qin G, Yao SK. Alteration of fecal tryptophan metabolism correlates with shifted microbiota and may be involved in pathogenesis of colorectal cancer. World J Gastroenterol 2020; 26:7173-7190. [PMID: 33362375 PMCID: PMC7723673 DOI: 10.3748/wjg.v26.i45.7173] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 10/12/2020] [Accepted: 11/02/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gut tryptophan (Trp) metabolites are produced by microbiota and/or host metabolism. Some of them have been proven to promote or inhibit colorectal cancer (CRC) in vitro and animal models. We hypothesized that there is an alteration of gut Trp metabolism mediated by microbiota and that it might be involved in the pathogenesis of cancer in patients with CRC. AIM To investigate the features of Trp metabolism in CRC and the correlation between fecal Trp metabolites and gut microbiota. METHODS Seventy-nine patients with colorectal neoplastic lesions (33 with colon adenoma and 46 with sporadic CRC) and 38 healthy controls (HCs) meeting the inclusion and exclusion criteria were included in the study. Their demographic and clinical features were collected. Fecal Trp, kynurenine (KYN), and indoles (metabolites of Trp metabolized by gut microbiota) were examined by ultraperformance liquid chromatography coupled to tandem mass spectrometry. Gut barrier marker and indoleamine 2,3-dioxygenase 1 (IDO1) mRNA were analyzed by quantitative real-time polymerase chain reaction. Zonula occludens-1 (ZO-1) protein expression was analyzed by immunohistochemistry. The gut microbiota was detected by 16S ribosomal RNA gene sequencing. Correlations between fecal metabolites and other parameters were examined in all patients. RESULTS The absolute concentration of KYN [1.51 (0.70, 3.46) nmol/g vs 0.81 (0.64, 1.57) nmol/g, P = 0.036] and the ratio of KYN to Trp [7.39 (4.12, 11.72) × 10-3 vs 5.23 (1.86, 7.99) × 10-3, P = 0.032] were increased in the feces of patients with CRC compared to HCs, while the indoles to Trp ratio was decreased [1.34 (0.70, 2.63) vs 2.46 (1.25, 4.10), P = 0.029]. The relative ZO-1 mRNA levels in patients with CRC (0.27 ± 0.24) were significantly lower than those in HCs (1.00 ± 0.31) (P < 0.001), and the relative IDO1 mRNA levels in patients with CRC [1.65 (0.47-2.46)] were increased (P = 0.035). IDO1 mRNA levels were positively associated with the KYN/Trp ratio (r = 0.327, P = 0.003). ZO-1 mRNA and protein levels were positively correlated with the indoles/Trp ratio (P = 0.035 and P = 0.009, respectively). In addition, the genera Asaccharobacter (Actinobacteria) and Parabacteroides (Bacteroidetes), and members of the phylum Firmicutes (Clostridium XlVb, Fusicatenibacter, Anaerofilum, and Anaerostipes) decreased in CRC and exhibited a positive correlation with indoles in all subjects. CONCLUSION Alteration of fecal Trp metabolism mediated by microbiota is associated with intestinal barrier function and tissue Trp metabolism, and may be involved in the pathogenesis of CRC.
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Affiliation(s)
- Xi-Zhen Sun
- Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Dong-Yan Zhao
- Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Yuan-Chen Zhou
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
- Peking University China-Japan Friendship School of Clinical Medicine, Peking University, Beijing 100029, China
| | - Qian-Qian Wang
- Peking University China-Japan Friendship School of Clinical Medicine, Peking University, Beijing 100029, China
| | - Geng Qin
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Shu-Kun Yao
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
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26
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Effect of Tryptophan-Derived AhR Ligands, Kynurenine, Kynurenic Acid and FICZ, on Proliferation, Cell Cycle Regulation and Cell Death of Melanoma Cells-In Vitro Studies. Int J Mol Sci 2020; 21:ijms21217946. [PMID: 33114713 PMCID: PMC7663343 DOI: 10.3390/ijms21217946] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 10/20/2020] [Accepted: 10/24/2020] [Indexed: 12/18/2022] Open
Abstract
Tryptophan metabolites: kynurenine (KYN), kynurenic acid (KYNA) and 6-formylindolo[3,2-b]carbazole (FICZ) are considered aryl hydrocarbon receptor (AhR) ligands. AhR is mainly expressed in barrier tissues, including skin, and is involved in various physiological and pathological processes in skin. We studied the effect of KYN, KYNA and FICZ on melanocyte and melanoma A375 and RPMI7951 cell toxicity, proliferation and cell death. KYN and FICZ inhibited DNA synthesis in both melanoma cell lines, but RPMI7951 cells were more resistant to pharmacological treatment. Tested compounds were toxic to melanoma cells but not to normal human adult melanocytes. Changes in the protein level of cyclin D1, CDK4 and retinoblastoma tumor suppressor protein (Rb) phosphorylation revealed different mechanisms of action of individual AhR ligands. Importantly, all tryptophan metabolites induced necrosis, but only KYNA and FICZ promoted apoptosis in melanoma A375 cells. This effect was not observed in RPMI7951 cells. KYN, KYNA and FICZ in higher concentrations inhibited the protein level of AhR but did not affect the gene expression. To conclude, despite belonging to the group of AhR ligands, KYN, KYNA and FICZ exerted different effects on proliferation, toxicity and induction of cell death in melanoma cells in vitro.
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27
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Quon T, Lin LC, Ganguly A, Tobin AB, Milligan G. Therapeutic Opportunities and Challenges in Targeting the Orphan G Protein-Coupled Receptor GPR35. ACS Pharmacol Transl Sci 2020; 3:801-812. [PMID: 33073184 PMCID: PMC7551713 DOI: 10.1021/acsptsci.0c00079] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Indexed: 02/07/2023]
Abstract
GPR35 is a class A, rhodopsin-like G protein-coupled receptor (GPCR) first identified more than 20 years ago. In the intervening period, identification of strong expression in the lower intestine and colon, in a variety of immune cells including monocytes and a variety of dendritic cells, and in dorsal root ganglia has suggested potential therapeutic opportunities in targeting this receptor in a range of conditions. GPR35 is, however, unusual in a variety of ways that challenge routes to translation. These include the following: (i) Although a substantial range and diversity of endogenous ligands have been suggested as agonist partners for this receptor, it officially remains defined as an "orphan" GPCR. (ii) Humans express two distinct protein isoform sequences, while rodents express only a single form. (iii) The pharmacologies of the human and rodent orthologues of GPR35 are very distinct, with variation between rat and mouse GPR35 being as marked as that between either of these species and the human forms. Herein we provide perspectives on each of the topics above as well as suggesting ways to overcome the challenges currently hindering potential translation. These include a better understanding of the extent and molecular basis for species selective GPR35 pharmacology and the production of novel mouse models in which both "on-target" and "off-target" effects of presumptive GPR35 ligands can be better defined, as well as a clear understanding of the human isoform expression profile and its significance at both tissue and individual cell levels.
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Affiliation(s)
- Tezz Quon
- Centre for Translational Pharmacology,
Institute of Molecular Cell and Systems Biology, College of Medical,
Veterinary and Life Sciences, University
of Glasgow, Glasgow G12 8QQ, United Kingdom of Great
Britain and Northern Ireland
| | - Li-Chiung Lin
- Centre for Translational Pharmacology,
Institute of Molecular Cell and Systems Biology, College of Medical,
Veterinary and Life Sciences, University
of Glasgow, Glasgow G12 8QQ, United Kingdom of Great
Britain and Northern Ireland
| | - Amlan Ganguly
- Centre for Translational Pharmacology,
Institute of Molecular Cell and Systems Biology, College of Medical,
Veterinary and Life Sciences, University
of Glasgow, Glasgow G12 8QQ, United Kingdom of Great
Britain and Northern Ireland
| | - Andrew B. Tobin
- Centre for Translational Pharmacology,
Institute of Molecular Cell and Systems Biology, College of Medical,
Veterinary and Life Sciences, University
of Glasgow, Glasgow G12 8QQ, United Kingdom of Great
Britain and Northern Ireland
| | - Graeme Milligan
- Centre for Translational Pharmacology,
Institute of Molecular Cell and Systems Biology, College of Medical,
Veterinary and Life Sciences, University
of Glasgow, Glasgow G12 8QQ, United Kingdom of Great
Britain and Northern Ireland
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28
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Díaz-Velasco S, González A, Peña FJ, Estévez M. Noxious effects of selected food-occurring oxidized amino acids on differentiated CACO-2 intestinal human cells. Food Chem Toxicol 2020; 144:111650. [PMID: 32745570 DOI: 10.1016/j.fct.2020.111650] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 07/21/2020] [Accepted: 07/23/2020] [Indexed: 12/27/2022]
Abstract
The harmful effects of food-occurring oxidized amino acids, namely, aminoadipic acid (AAA), dityrosine (DTYR), L-kynurenine (KN), kynurenic acid (KA) and 3-nitrotyrosine (3NT), were studied on differentiated CACO-2 cells by flow cytometry and quantification of glutathione (GSH), and allysine. Cells were exposed to food-relevant doses (200 μM) of each compound for 4 or 72h and compared to a control (no stimulated cells). All oxidized amino acids induced apoptosis and results indicated that underlying mechanisms depended on the chemical nature of the species. AAA, KN and KA caused ROS generation and severe oxidative stress in 96%, 98% and 89% of exposed cells (77% in control cells), leading to significant GSH depletion and allysine accretion (1.5, 1.5 and 1.6 nmol allysine/mg protein, respectively at 4h; control: 0.22 nmol/mg protein; p < 0.05). DTYR and 3NT induced significant apoptosis to 29% and 25% of cells (control: 16%; p < 0.05) and necrosis to 28% and 26% of cells (control: 23%) at 72h by ROS-independent mechanisms. KN and KA were found to induce a cycle arrest effect on CACO-2 cells. These findings emphasize the potential harmful effects of the intake of oxidized proteins and amino acids and urge the necessity of carrying out further molecular studies.
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Affiliation(s)
- S Díaz-Velasco
- IPROCAR Research Institute, TECAL Research Group, University of Extremadura, 10003, Cáceres, Spain
| | - A González
- Institute of Molecular Pathology Biomarkers, University of Extremadura, 10003, Cáceres, Spain
| | - F J Peña
- Spermatology Laboratory, University of Extremadura, 10003, Cáceres, Spain
| | - Mario Estévez
- IPROCAR Research Institute, TECAL Research Group, University of Extremadura, 10003, Cáceres, Spain.
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29
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Yao H, Lv Y, Bai X, Yu Z, Liu X. Prognostic value of CXCL17 and CXCR8 expression in patients with colon cancer. Oncol Lett 2020; 20:2711-2720. [PMID: 32782587 PMCID: PMC7400977 DOI: 10.3892/ol.2020.11819] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 05/27/2020] [Indexed: 01/03/2023] Open
Abstract
C-X-C motif chemokine ligand 17 (CXCL17) is a mucous chemokine and its expression is highly correlated with that of G protein-coupled receptor 35 (GPR35), which has been confirmed as its receptor and named C-X-C motif chemokine receptor 8 (CXCR8). CXCL17 is upregulated in several types of cancer. However, the biological role of this chemokine in colon cancer remains unknown. In the present study, the expression levels of CXCL17 and CXCR8 were examined using immunohistochemistry in 101 colon cancer tissues and 79 healthy tumour-adjacent tissues. CXCL17 and CXCR8 expression levels were increased in the colon cancer samples compared with tumour-adjacent samples. Patients with high CXCL17 expression had longer overall survival (OS) compared with patients with low expression of CXCL17 (log-rank test; P=0.027). However, CXCR8 expression, but not CXCL17, was an independent prognostic factor for OS in patients with colon cancer. The expression of CXCR8 correlated positively with that of CXCL17 in colon cancer samples (ρ=0.295; P=0.003). Furthermore, the combined high expression of CXCL17 and CXCR8 was a significant independent prognostic factor for OS in patients with colon cancer (P=0.001). In subgroups with a TNM stage of I–II, the patients with combined high expression of CXCL17 and CXCR8 had a longer survival compared with those without combined high expression (P=0.001). However, this difference was not observed in subgroups with a TNM stage of III–IV. Collectively, these findings suggest that CXCL17/CXCR8 signalling may be involved in colon cancer and contribute to improved patient outcomes.
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Affiliation(s)
- Hongyan Yao
- Department of Pharmacology, School of Basic Medical Sciences, Jinzhou Medical University, Jinzhou, Liaoning 121001, P.R. China.,Nuclear Medicine Department, Jinzhou Central Hospital, Jinzhou, Liaoning 121001, P.R. China
| | - Yufeng Lv
- Department of Respiration and Critical Care, The Affiliated Hongqi Hospital of Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
| | - Xuefeng Bai
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Zhaojin Yu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Xiaojian Liu
- Department of Pharmacology, School of Basic Medical Sciences, Jinzhou Medical University, Jinzhou, Liaoning 121001, P.R. China
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30
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Pflügler S, Svinka J, Scharf I, Crncec I, Filipits M, Charoentong P, Tschurtschenthaler M, Kenner L, Awad M, Stift J, Schernthanner M, Bischl R, Herndler-Brandstetter D, Glitzner E, Moll HP, Casanova E, Timelthaler G, Sibilia M, Gnant M, Lax S, Thaler J, Müller M, Strobl B, Mohr T, Kaser A, Trajanoski Z, Heller G, Eferl R. IDO1 + Paneth cells promote immune escape of colorectal cancer. Commun Biol 2020; 3:252. [PMID: 32444775 PMCID: PMC7244549 DOI: 10.1038/s42003-020-0989-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 04/10/2020] [Indexed: 02/07/2023] Open
Abstract
Tumors have evolved mechanisms to escape anti-tumor immunosurveillance. They limit humoral and cellular immune activities in the stroma and render tumors resistant to immunotherapy. Sensitizing tumor cells to immune attack is an important strategy to revert immunosuppression. However, the underlying mechanisms of immune escape are still poorly understood. Here we discover Indoleamine-2,3-dioxygenase-1 (IDO1)+ Paneth cells in the stem cell niche of intestinal crypts and tumors, which promoted immune escape of colorectal cancer (CRC). Ido1 expression in Paneth cells was strictly Stat1 dependent. Loss of IDO1+ Paneth cells in murine intestinal adenomas with tumor cell-specific Stat1 deletion had profound effects on the intratumoral immune cell composition. Patient samples and TCGA expression data suggested corresponding cells in human colorectal tumors. Thus, our data uncovered an immune escape mechanism of CRC and identify IDO1+ Paneth cells as a target for immunotherapy.
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Affiliation(s)
- Sandra Pflügler
- Institute of Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, 1090, Vienna, Austria
| | - Jasmin Svinka
- Institute of Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, 1090, Vienna, Austria
| | - Irene Scharf
- Institute of Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, 1090, Vienna, Austria
| | - Ilija Crncec
- Institute of Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, 1090, Vienna, Austria
| | - Martin Filipits
- Institute of Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, 1090, Vienna, Austria
| | - Pornpimol Charoentong
- Institute of Bioinformatics, Medical University Innsbruck, Biocenter, 6020, Innsbruck, Austria
- Department of Medical Oncology, National Center for Tumor diseases, University Hospital Heidelberg, 69120, Heidelberg, Germany
- German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
| | - Markus Tschurtschenthaler
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK
- Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, 81675, Munich, Germany
| | - Lukas Kenner
- Ludwig Boltzmann Institute for Cancer Research LBICR, 1090, Vienna, Austria
- Institute of Clinical Pathology, Medical University of Vienna, 1090, Vienna, Austria
- Department of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, 1210, Vienna, Austria
| | - Monira Awad
- Institute of Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, 1090, Vienna, Austria
| | - Judith Stift
- Institute of Clinical Pathology, Medical University of Vienna, 1090, Vienna, Austria
| | - Marina Schernthanner
- Institute of Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, 1090, Vienna, Austria
| | - Romana Bischl
- Institute of Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, 1090, Vienna, Austria
| | | | - Elisabeth Glitzner
- Institute of Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, 1090, Vienna, Austria
| | - Herwig P Moll
- Department of Physiology, Center of Physiology and Pharmacology, Comprehensive Cancer Center (CCC), Medical University of Vienna, 1090, Vienna, Austria
| | - Emilio Casanova
- Ludwig Boltzmann Institute for Cancer Research LBICR, 1090, Vienna, Austria
- Department of Physiology, Center of Physiology and Pharmacology, Comprehensive Cancer Center (CCC), Medical University of Vienna, 1090, Vienna, Austria
| | - Gerald Timelthaler
- Institute of Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, 1090, Vienna, Austria
| | - Maria Sibilia
- Institute of Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, 1090, Vienna, Austria
| | - Michael Gnant
- Department of Surgery, Breast Health Center, Comprehensive Cancer Center, Medical University of Vienna, 1090, Vienna, Austria
| | - Sigurd Lax
- Department of Pathology, Hospital Graz II, 8020, Graz, Austria
- Institute of Pathology and Molecular Pathology, Johannes Kepler University, 4040, Linz, Austria
| | - Josef Thaler
- Department of Internal Medicine IV, Klinikum Wels-Grieskirchen, 4600, Wels, Austria
| | - Mathias Müller
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210, Vienna, Austria
| | - Birgit Strobl
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210, Vienna, Austria
| | - Thomas Mohr
- Institute of Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, 1090, Vienna, Austria
| | - Arthur Kaser
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK
| | - Zlatko Trajanoski
- Institute of Bioinformatics, Medical University Innsbruck, Biocenter, 6020, Innsbruck, Austria
| | - Gerwin Heller
- Division of Oncology, Medical University of Vienna and Comprehensive Cancer Center, 1090, Vienna, Austria
| | - Robert Eferl
- Institute of Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, 1090, Vienna, Austria.
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31
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Zuhra K, Augsburger F, Majtan T, Szabo C. Cystathionine-β-Synthase: Molecular Regulation and Pharmacological Inhibition. Biomolecules 2020; 10:E697. [PMID: 32365821 PMCID: PMC7277093 DOI: 10.3390/biom10050697] [Citation(s) in RCA: 146] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 04/24/2020] [Accepted: 04/27/2020] [Indexed: 12/11/2022] Open
Abstract
Cystathionine-β-synthase (CBS), the first (and rate-limiting) enzyme in the transsulfuration pathway, is an important mammalian enzyme in health and disease. Its biochemical functions under physiological conditions include the metabolism of homocysteine (a cytotoxic molecule and cardiovascular risk factor) and the generation of hydrogen sulfide (H2S), a gaseous biological mediator with multiple regulatory roles in the vascular, nervous, and immune system. CBS is up-regulated in several diseases, including Down syndrome and many forms of cancer; in these conditions, the preclinical data indicate that inhibition or inactivation of CBS exerts beneficial effects. This article overviews the current information on the expression, tissue distribution, physiological roles, and biochemistry of CBS, followed by a comprehensive overview of direct and indirect approaches to inhibit the enzyme. Among the small-molecule CBS inhibitors, the review highlights the specificity and selectivity problems related to many of the commonly used "CBS inhibitors" (e.g., aminooxyacetic acid) and provides a comprehensive review of their pharmacological actions under physiological conditions and in various disease models.
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Affiliation(s)
- Karim Zuhra
- Chair of Pharmacology, Section of Medicine, University of Fribourg, 1702 Fribourg, Switzerland; (K.Z.); (F.A.)
| | - Fiona Augsburger
- Chair of Pharmacology, Section of Medicine, University of Fribourg, 1702 Fribourg, Switzerland; (K.Z.); (F.A.)
| | - Tomas Majtan
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA;
| | - Csaba Szabo
- Chair of Pharmacology, Section of Medicine, University of Fribourg, 1702 Fribourg, Switzerland; (K.Z.); (F.A.)
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Walczak K, Langner E, Szalast K, Makuch-Kocka A, Pożarowski P, Plech T. A Tryptophan Metabolite, 8-Hydroxyquinaldic Acid, Exerts Antiproliferative and Anti-Migratory Effects on Colorectal Cancer Cells. Molecules 2020; 25:molecules25071655. [PMID: 32260268 PMCID: PMC7181169 DOI: 10.3390/molecules25071655] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 03/31/2020] [Accepted: 04/02/2020] [Indexed: 12/24/2022] Open
Abstract
8-Hydroxyquinaldic acid, the end-metabolite of tryptophan, is well-known metal chelator; however, its role in humans, especially in cancer promotion and progression, has not been fully revealed. Importantly, 8-hydroxyquinaldic acid is the analog of kynurenic acid with evidenced antiproliferative activity towards various cancer cells. In this study, we revealed that 8-hydroxyquinaldic acid inhibited not only proliferation and mitochondrial activity in colon cancer HT-29 and LS-180 cells, but it also decreased DNA synthesis up to 90.9% for HT-29 cells and 76.1% for LS-180 cells. 8-Hydroxyquinaldic acid induced changes in protein expression of cell cycle regulators (CDK4, CDK6, cyclin D1, cyclin E) and CDKs inhibitors (p21 Waf1/Cip1, p27 Kip1), but the effect was dependent on the tested cell line. Moreover, 8-hydroxyquinaldic acid inhibited migration of colon cancer HT-29 and LS-180 cells and increased the expression of β-catenin and E-cadherin. Importantly, antiproliferative and anti-migratory concentrations of 8-hydroxyquinaldic acid were non-toxic in vitro and in vivo. We reported for the first time antiproliferative and anti-migratory activity of 8-hydroxyquinaldic acid against colon cancer HT-29 and LS-180 cells.
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Affiliation(s)
- Katarzyna Walczak
- Department of Pharmacology, Medical University of Lublin, Chodźki 4a, 20-093 Lublin, Poland; (E.L.); (K.S.); (A.M.-K.)
- Correspondence: (K.W.); (T.P.); Tel.: +48-81-448-6772 (T.P.)
| | - Ewa Langner
- Department of Pharmacology, Medical University of Lublin, Chodźki 4a, 20-093 Lublin, Poland; (E.L.); (K.S.); (A.M.-K.)
- Department of Medical Biology, Institute of Rural Health, Jaczewskiego 2, 20-090 Lublin, Poland
| | - Karolina Szalast
- Department of Pharmacology, Medical University of Lublin, Chodźki 4a, 20-093 Lublin, Poland; (E.L.); (K.S.); (A.M.-K.)
| | - Anna Makuch-Kocka
- Department of Pharmacology, Medical University of Lublin, Chodźki 4a, 20-093 Lublin, Poland; (E.L.); (K.S.); (A.M.-K.)
| | - Piotr Pożarowski
- Chair and Department of Clinical Immunology, Medical University of Lublin, Chodźki 4a, 20-093 Lublin, Poland;
| | - Tomasz Plech
- Department of Pharmacology, Medical University of Lublin, Chodźki 4a, 20-093 Lublin, Poland; (E.L.); (K.S.); (A.M.-K.)
- Correspondence: (K.W.); (T.P.); Tel.: +48-81-448-6772 (T.P.)
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Walczak K, Wnorowski A, Turski WA, Plech T. Kynurenic acid and cancer: facts and controversies. Cell Mol Life Sci 2020; 77:1531-1550. [PMID: 31659416 PMCID: PMC7162828 DOI: 10.1007/s00018-019-03332-w] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 09/30/2019] [Accepted: 10/08/2019] [Indexed: 12/17/2022]
Abstract
Kynurenic acid (KYNA) is an endogenous tryptophan metabolite exerting neuroprotective and anticonvulsant properties in the brain. However, its importance on the periphery is still not fully elucidated. KYNA is produced endogenously in various types of peripheral cells, tissues and by gastrointestinal microbiota. Furthermore, it was found in several products of daily human diet and its absorption in the digestive tract was evidenced. More recent studies were focused on the potential role of KYNA in carcinogenesis and cancer therapy; however, the results were ambiguous and the biological activity of KYNA in these processes has not been unequivocally established. This review aims to summarize the current views on the relationship between KYNA and cancer. The differences in KYNA concentration between physiological conditions and cancer, as well as KYNA production by both normal and cancer cells, will be discussed. The review also describes the effect of KYNA on cancer cell proliferation and the known potential molecular mechanisms of this activity.
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Affiliation(s)
- Katarzyna Walczak
- Department of Pharmacology, Medical University of Lublin, Chodźki 4a, 20-093, Lublin, Poland.
| | - Artur Wnorowski
- Department of Biopharmacy, Medical University of Lublin, Chodźki 4a, 20-093, Lublin, Poland
| | - Waldemar A Turski
- Department of Experimental and Clinical Pharmacology, Medical University of Lublin, Jaczewskiego 8, 20-090, Lublin, Poland
| | - Tomasz Plech
- Department of Pharmacology, Medical University of Lublin, Chodźki 4a, 20-093, Lublin, Poland
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Chandrapalan S, Arasaradnam RP. Urine as a biological modality for colorectal cancer detection. Expert Rev Mol Diagn 2020; 20:489-496. [PMID: 32130868 DOI: 10.1080/14737159.2020.1738928] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Introduction: The increasing incidence of colorectal cancer (CRC) in young adults warrants early and preferably noninvasive diagnostic modalities. Although the current stool-based assays have had good performance indicators for CRC detection, the overall poor uptake remains a challenging issue. However, alternative blood and urine markers are emerging.Areas covered: This paper discusses the various urinary biomarkers available for the detection of CRC. The more commonly encountered drawbacks are the small number of studies and the size of the study population. We discuss the role of microRNA and ProstaglandinE2 in CRC detection. The emergence of new, low-cost technologies, specifically in the detection of volatile organic compounds (VOCs), presents a promising future. We postulate possible mechanisms for the origin of these VOCs in urine and their role in carcinogenesis.Expert opinion: Urinary biomarkers provide an alternative option to the stool-based screening tests. MicroRNA and ProstaglandinE2 have shown utility in CRC detection. Evidence so far suggests that VOCs could also be a potential biomarker for the detection of CRC. In addition to its interaction within the colon lumen, this altered 'VOC signature' might also play a role in carcinogenesis. Low-cost technology may enable such diagnostic methods to be utilized at the point of care.
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Affiliation(s)
- Subashini Chandrapalan
- Department of Gastroenterology, University Hospital of Coventry and Warwickshire, Coventry, UK
| | - Ramesh P Arasaradnam
- Department of Gastroenterology, University Hospital of Coventry and Warwickshire, Coventry, UK.,Warwick Medical School, University of Warwick, Coventry, UK.,Health, Biological & Experimental Sciences, University of Coventry, Coventry, UK.,School of Health Sciences, University of Leicester, Leicester, UK
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Belghasem M, Roth D, Richards S, Napolene MA, Walker J, Yin W, Arinze N, Lyle C, Spencer C, Francis JM, Thompson C, Andry C, Whelan SA, Lee N, Ravid K, Chitalia VC. Metabolites in a mouse cancer model enhance venous thrombogenicity through the aryl hydrocarbon receptor-tissue factor axis. Blood 2019; 134:2399-2413. [PMID: 31877217 PMCID: PMC6933294 DOI: 10.1182/blood.2019001675] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 10/17/2019] [Indexed: 12/13/2022] Open
Abstract
Patients with malignancy are at 4- to 7-fold higher risk of venous thromboembolism (VTE), a potentially fatal, yet preventable complication. Although general mechanisms of thrombosis are enhanced in these patients, malignancy-specific triggers and their therapeutic implication remain poorly understood. Here we examined a colon cancer-specific VTE model and probed a set of metabolites with prothrombotic propensity in the inferior vena cava (IVC) ligation model. Athymic mice injected with human colon adenocarcinoma cells exhibited significantly higher IVC clot weights, a biological readout of venous thrombogenicity, compared with the control mice. Targeted metabolomics analysis of plasma of mice revealed an increase in the blood levels of kynurenine and indoxyl sulfate (tryptophan metabolites) in xenograft-bearing mice, which correlated positively with the increase in the IVC clot size. These metabolites are ligands of aryl hydrocarbon receptor (AHR) signaling. Accordingly, plasma from the xenograft-bearing mice activated the AHR pathway and augmented tissue factor (TF) and plasminogen activator inhibitor 1 (PAI-1) levels in venous endothelial cells in an AHR-dependent manner. Consistent with these findings, the endothelium from the IVC of xenograft-bearing animals revealed nuclear AHR and upregulated TF and PAI-1 expression, telltale signs of an activated AHR-TF/PAI-1 axis. Importantly, pharmacological inhibition of AHR activity suppressed TF and PAI-1 expression in endothelial cells of the IVC and reduced clot weights in both kynurenine-injected and xenograft-bearing mice. Together, these data show dysregulated tryptophan metabolites in a mouse cancer model, and they reveal a novel link between these metabolites and the control of the AHR-TF/PAI-1 axis and VTE in cancer.
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Affiliation(s)
| | - Daniel Roth
- Department of Pathology and Laboratory Medicine and
| | - Sean Richards
- Department of Medicine, Boston University School of Medicine, Boston, MA
| | | | - Joshua Walker
- Department of Medicine, Boston University School of Medicine, Boston, MA
| | - Wenqing Yin
- Department of Medicine, Boston University School of Medicine, Boston, MA
| | - Nkiruka Arinze
- Department of Surgery, Boston University Medical Center, Boston, MA
| | - Chimera Lyle
- Department of Medicine, Boston University School of Medicine, Boston, MA
| | | | - Jean M Francis
- Department of Medicine, Boston University School of Medicine, Boston, MA
| | - Cristal Thompson
- Department of Medicine, Boston University School of Medicine, Boston, MA
- Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA
| | | | | | - Norman Lee
- Chemical Instrumentation Center, Boston University, Boston, MA
| | - Katya Ravid
- Department of Medicine, Boston University School of Medicine, Boston, MA
- Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA
| | - Vipul C Chitalia
- Department of Medicine, Boston University School of Medicine, Boston, MA
- Veterans Affairs Boston Healthcare System, Boston, MA; and
- Global Co-Creation Labs, Institute of Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA
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Trikha P, Lee DA. The role of AhR in transcriptional regulation of immune cell development and function. Biochim Biophys Acta Rev Cancer 2019; 1873:188335. [PMID: 31816350 DOI: 10.1016/j.bbcan.2019.188335] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 12/02/2019] [Accepted: 12/02/2019] [Indexed: 12/13/2022]
Abstract
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcriptional factor (TF) that is a member of the Per-Arnt-Sim family of proteins. AhR regulates diverse processes, including malignant transformation, hematopoietic cell development, and fate determination of immune cell lineages. Moreover, AhR forms a crucial link between innate and adaptive arms of the immune system. Malignant cells frequently evolve multiple mechanisms for suppressing tumor-specific responses, including the induction of suppressive pathways involving AhR and its metabolic byproducts in the tumor microenvironment that promote immune evasion and tumor progression. Thus, interest is high in further defining the role of AhR in carcinogenesis and immune development and regulation, particularly regarding the therapeutic interventions that unleash immune responses to cancer cells. Here, we provide an overview of the role of AhR in the regulation of innate and adaptive immune response and discuss the implications of targeting this pathway to augment the immune response in cancer patients.
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Affiliation(s)
- Prashant Trikha
- Cellular Therapy & Cancer Immunotherapy Program, Center for Childhood Cancer & Blood Diseases, WA-4112 Abigail Wexner Research Institute, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, United States of America.
| | - Dean A Lee
- Cellular Therapy & Cancer Immunotherapy Program, Center for Childhood Cancer & Blood Diseases, WA-4112 Abigail Wexner Research Institute, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, United States of America
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Dudzińska E, Szymona K, Kloc R, Gil-Kulik P, Kocki T, Świstowska M, Bogucki J, Kocki J, Urbanska EM. Increased expression of kynurenine aminotransferases mRNA in lymphocytes of patients with inflammatory bowel disease. Therap Adv Gastroenterol 2019; 12:1756284819881304. [PMID: 31666808 PMCID: PMC6801885 DOI: 10.1177/1756284819881304] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 09/18/2019] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Complex interaction of genetic defects with environmental factors seems to play a substantial role in the pathogenesis of inflammatory bowel disease (IBD). Accumulating data implicate a potential role of disturbed tryptophan metabolism in IBD. Kynurenic acid (KYNA), a derivative of tryptophan (TRP) along the kynurenine (KYN) pathway, displays cytoprotective and immunomodulating properties, whereas 3-OH-KYN is a cytotoxic compound, generating free radicals. METHODS The expression of lymphocytic mRNA encoding enzymes synthesizing KYNA (KAT I-III) and serum levels of TRP and its metabolites were evaluated in 55 patients with IBD, during remission or relapse [27 patients with ulcerative colitis (UC) and 28 patients with Crohn's disease (CD)] and in 50 control individuals. RESULTS The increased expression of KAT1 and KAT3 mRNA characterized the entire cohorts of patients with UC and CD, as well as relapse-remission subsets. Expression of KAT2 mRNA was enhanced in patients with UC and in patients with CD in remission. In the entire cohorts of UC or CD, TRP levels were lower, whereas KYN, KYNA and 3-OH-KYN were not altered. When analysed in subsets of patients with UC and CD (active phase-remission), KYNA level was significantly lower during remission than relapse, yet not versus control. Functionally, in the whole groups of patients with UC or CD, the TRP/KYN ratio has been lower than control, whereas KYN/KYNA and KYNA/3-OH-KYN ratios were not altered. The ratio KYN/3-OH-KYN increased approximately two-fold among all patients with CD; furthermore, patients with CD with relapse, manifested a significantly higher KYNA/3-OH-KYN ratio than patients in remission. CONCLUSION The presented data indicate that IBD is associated with an enhanced expression of genes encoding KYNA biosynthetic enzymes in lymphocytes; however, additional mechanisms appear to influence KYNA levels. Higher metabolic conversion of serum TRP in IBD seems to be followed by the functional shift of KYN pathway towards the arm producing KYNA during exacerbation. We propose that KYNA, possibly via interaction with aryl hydrocarbon receptor or G-protein-coupled orphan receptor 35, may serve as a counter-regulatory mechanism, decreasing cytotoxicity and inflammation in IBD. Further longitudinal studies evaluating the individual dynamics of TRP and KYN pathway in patients with IBD, as well as the nature of precise mechanisms regulating KYNA synthesis, should be helpful in better understanding the processes underlying the observed changes.
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Affiliation(s)
- Ewa Dudzińska
- Medical University of Lublin, Chodźki 1 Street,
Lublin, 20-093, Lubelskie, Poland
| | - Kinga Szymona
- Medical University of Lublin, Lublin, Lubelskie,
Poland
| | - Renata Kloc
- Department of Experimental and Clinical
Pharmacology, Medical University of Lublin, Lublin, Lubelskie, Poland
| | - Paulina Gil-Kulik
- Department of Clinical Genetics, Medical
University of Lublin, Lublin, Lubelskie, Poland
| | - Tomasz Kocki
- Department of Experimental and Clinical
Pharmacology, Medical University of Lublin, Lublin, Lubelskie, Poland
| | - Małgorzata Świstowska
- Department of Clinical Genetics, Medical
University of Lublin, Lublin, Lubelskie, Poland
| | - Jacek Bogucki
- Department of Clinical Genetics, Medical
University of Lublin, Lublin, Lubelskie, Poland
| | - Janusz Kocki
- Department of Clinical Genetics, Medical
University of Lublin, Lublin, Lubelskie, Poland
| | - Ewa M. Urbanska
- Department of Experimental and Clinical
Pharmacology, Medical University of Lublin, Lublin, Lubelskie, Poland
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Bishnupuri KS, Alvarado DM, Khouri AN, Shabsovich M, Chen B, Dieckgraefe BK, Ciorba MA. IDO1 and Kynurenine Pathway Metabolites Activate PI3K-Akt Signaling in the Neoplastic Colon Epithelium to Promote Cancer Cell Proliferation and Inhibit Apoptosis. Cancer Res 2019; 79:1138-1150. [PMID: 30679179 DOI: 10.1158/0008-5472.can-18-0668] [Citation(s) in RCA: 148] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 11/27/2018] [Accepted: 01/16/2019] [Indexed: 12/12/2022]
Abstract
The tryptophan-metabolizing enzyme indoleamine 2,3 dioxygenase 1 (IDO1) is frequently overexpressed in epithelial-derived malignancies, where it plays a recognized role in promoting tumor immune tolerance. We previously demonstrated that the IDO1-kynurenine pathway (KP) also directly supports colorectal cancer growth by promoting activation of β-catenin and driving neoplastic growth in mice lacking intact adaptive immunity. In this study, we sought to delineate the specific role of epithelial IDO1 in colon tumorigenesis and define how IDO1 and KP metabolites interact with pivotal neoplastic signaling pathways of the colon epithelium. We generated a novel intestinal epithelial-specific IDO1 knockout mouse and utilized established colorectal cancer cell lines containing β-catenin-stabilizing mutations, human colorectal cancer samples, and human-derived epithelial organoids (colonoids and tumoroids). Mice with intestinal epithelial-specific knockout of IDO1 developed fewer and smaller tumors than wild-type littermates in a model of inflammation-driven colon tumorigenesis. Moreover, their tumors exhibited reduced nuclear β-catenin and neoplastic proliferation but increased apoptosis. Mechanistically, KP metabolites (except kynurenic acid) rapidly activated PI3K-Akt signaling in the neoplastic epithelium to promote nuclear translocation of β-catenin, cellular proliferation, and resistance to apoptosis. Together, these data define a novel cell-autonomous function and mechanism by which IDO1 activity promotes colorectal cancer progression. These findings may have implications for the rational design of new clinical trials that exploit a synergy of IDO1 inhibitors with conventional cancer therapies for which Akt activation provides resistance such as radiation.Significance: This study identifies a new mechanistic link between IDO1 activity and PI3K/AKT signaling, both of which are important pathways involved in cancer growth and resistance to cancer therapy.
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Affiliation(s)
- Kumar S Bishnupuri
- Division of Gastroenterology and the Inflammatory Bowel Diseases Center, Washington University School of Medicine, St. Louis, Missouri.
| | - David M Alvarado
- Division of Gastroenterology and the Inflammatory Bowel Diseases Center, Washington University School of Medicine, St. Louis, Missouri
| | - Alexander N Khouri
- Division of Gastroenterology and the Inflammatory Bowel Diseases Center, Washington University School of Medicine, St. Louis, Missouri
| | - Mark Shabsovich
- Division of Gastroenterology and the Inflammatory Bowel Diseases Center, Washington University School of Medicine, St. Louis, Missouri
| | - Baosheng Chen
- Division of Gastroenterology and the Inflammatory Bowel Diseases Center, Washington University School of Medicine, St. Louis, Missouri
| | - Brian K Dieckgraefe
- Division of Gastroenterology and the Inflammatory Bowel Diseases Center, Washington University School of Medicine, St. Louis, Missouri
| | - Matthew A Ciorba
- Division of Gastroenterology and the Inflammatory Bowel Diseases Center, Washington University School of Medicine, St. Louis, Missouri.
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Cheng X, Liu X, Liu X, Guo Z, Sun H, Zhang M, Ji Z, Sun W. Metabolomics of Non-muscle Invasive Bladder Cancer: Biomarkers for Early Detection of Bladder Cancer. Front Oncol 2018; 8:494. [PMID: 30450336 PMCID: PMC6224486 DOI: 10.3389/fonc.2018.00494] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Accepted: 10/11/2018] [Indexed: 12/31/2022] Open
Abstract
Background: Clinical outcomes of bladder cancer (BC) are tightly associated with the stage and grade of the initial diagnosis of BC because early detection is clearly important for patients with BC. However, the diagnostic capability of current detection methods, such as urinary cytology, cystoscopy, imageology method, and several urine-based tests, is inadequate for early detection of BC. The objective of our study is to discover novel biomarkers for detecting BC at an early stage, called non-muscle invasive (NMI) BC, using liquid chromatography-high resolution mass spectrometry (LC-HRMS)-based metabolomics. Methods: First, morning midstream urine samples were collected from healthy adult and NMIBC patients. The LC-HRMS-based metabolomics were applied to distinguish the NMIBC group without hematuria from the controls (gender- and age-matched volunteers with normal clinically healthy index), low-grade NMIBC from the controls, and high-grade from low-grade NMIBC. Results: A total of 284 subjects were enrolled in our study including 117 healthy adults, 80 NMIBC patients without hematuria, and 87 NMIBC patients with hematuria. The metabolite panel including dopamine 4-sulfate, MG00/1846Z,9Z,12Z,15Z/00, aspartyl-histidine, and tyrosyl-methionine was found in a discovery set, which showed the predictive ability to distinguish the NMIBC group from the control group with an area under the curve (AUC) of 0.838 in an external validation set. The AUC of the panel for low-grade NMIBC samples, which consisted of 3-hydroxy-cis-5-tetradecenoylcarnitine, 6-ketoestriol, beta-cortolone, tetrahydrocorticosterone, and heptylmalonic acid, was 0.899. The sensitivity and specificity were 0.881 and 0.786, respectively. The AUC of the panel for distinction of low-grade NMIBC with and without hematuria against high-grade NMIBC with and without hematuria were 0.827 and 0.755, respectively. In addition, metabolites involved in tryptophan metabolism were upregulated in the urine of high-grade NMIBC patients when compared with low-grade NMIBC patients with the presence or absence of hematuria. Conclusion: The NMIBC urine metabolic profiling was able to assist in the early detection of BC. Panels of metabolites were discovered to have a potential value for high-grade NMIBC and low-grade NMIBC diagnosis as well as for NMIBC grading distinction.
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Affiliation(s)
- Xiangming Cheng
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Xiaoyan Liu
- Core Facility of Instrument, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Xiang Liu
- Core Facility of Instrument, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Zhengguang Guo
- Core Facility of Instrument, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Haidan Sun
- Core Facility of Instrument, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Mingxin Zhang
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Zhigang Ji
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Wei Sun
- Core Facility of Instrument, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/School of Basic Medicine, Peking Union Medical College, Beijing, China
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Fate and distribution of kynurenic acid administered as beverage. Pharmacol Rep 2018; 70:1089-1096. [PMID: 30308459 DOI: 10.1016/j.pharep.2018.05.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 04/29/2018] [Accepted: 05/28/2018] [Indexed: 01/07/2023]
Abstract
BACKGROUND Kynurenic acid (KYNA) is a biologically active metabolite of tryptophan exerting action on several receptors located in the brain and periphery. KYNA can be synthesized endogenously or supplied in the diet. It was documented that KYNA is present in various types of food. However, its presence in beverages was not yet investigated. Here, we measured content of KYNA in tea and coffee as well as analyzed distribution and fate of intragastrically administered labelled KYNA in mice. METHODS 16 and 13 studied samples of tea and coffee, respectively were of commercial origin. Tea and coffee infusions were prepared according to the producers' guidelines. KYNA content in beverages was measured by means of HPLC detection. Adult male mice were used for analysis of fate of intragastrically administered labelled KYNA and collected samples were analyzed using liquid scintillation counter. RESULTS KYNA was identified in all studied beverages. Amounts of KYNA found in various types of beverages differed significantly. The highest content of KYNA in tea and coffee was 8.7 μg/100 ml and 0.63 μg/100 ml, respectively. It was found that KYNA administered intragastrically as a liquid is absorbed from the digestive system and readily excreted in urine. The atypical kinetics of KYNA distribution were found in intestinal content of cecum, where it appeared later and persisted longer than in other tissues. CONCLUSIONS Our data show that tea and coffee intake may contribute to KYNA content in the human organism. The distribution pattern of KYNA delivered as a liquid suggests that it either directly affects digestive system's functioning and intestinal microbiome composition, or participates in the whole body pool of KYNA.
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Stone TW, McPherson M, Gail Darlington L. Obesity and Cancer: Existing and New Hypotheses for a Causal Connection. EBioMedicine 2018; 30:14-28. [PMID: 29526577 PMCID: PMC5952217 DOI: 10.1016/j.ebiom.2018.02.022] [Citation(s) in RCA: 162] [Impact Index Per Article: 23.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 02/12/2018] [Accepted: 02/23/2018] [Indexed: 02/07/2023] Open
Abstract
Existing explanations of obesity-associated cancer emphasise direct mutagenic effects of dietary components or hormonal imbalance. Some of these hypotheses are reviewed briefly, but recent evidence suggests a major role for chronic inflammation in cancer risk, possibly involving dietary content. These ideas include the inflammation-induced activation of the kynurenine pathway and its role in feeding and metabolism by activation of the aryl hydrocarbon receptor (AHR) and by modulating synaptic transmission in the brain. Evidence for a role of the kynurenine pathway in carcinogenesis then provides a potentially major link between obesity and cancer. A second new hypothesis is based on evidence that serine proteases can deplete cells of the tumour suppressors Deleted in Colorectal Cancer (DCC) and neogenin. These enzymes include mammalian chymotryptic proteases released by pro-inflammatory neutrophils and macrophages. Blood levels of chymotrypsin itself increase in parallel with food intake. The mechanistically similar bacterial enzyme subtilisin is widespread in the environment, animal probiotics, meat processing and cleaning products. Simple public health schemes in these areas, with selective serine protease inhibitors and AHR antagonists and could prevent a range of intestinal and other cancers.
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Affiliation(s)
- Trevor W Stone
- The Kennedy Institute, University of Oxford, Oxford OX3 7FY, UK; Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
| | - Megan McPherson
- School of Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
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Gao J, Xu K, Liu H, Liu G, Bai M, Peng C, Li T, Yin Y. Impact of the Gut Microbiota on Intestinal Immunity Mediated by Tryptophan Metabolism. Front Cell Infect Microbiol 2018; 8:13. [PMID: 29468141 PMCID: PMC5808205 DOI: 10.3389/fcimb.2018.00013] [Citation(s) in RCA: 829] [Impact Index Per Article: 118.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Accepted: 01/12/2018] [Indexed: 12/12/2022] Open
Abstract
The gut microbiota influences the health of the host, especially with regard to gut immune homeostasis and the intestinal immune response. In addition to serving as a nutrient enhancer, L-tryptophan (Trp) plays crucial roles in the balance between intestinal immune tolerance and gut microbiota maintenance. Recent discoveries have underscored that changes in the microbiota modulate the host immune system by modulating Trp metabolism. Moreover, Trp, endogenous Trp metabolites (kynurenines, serotonin, and melatonin), and bacterial Trp metabolites (indole, indolic acid, skatole, and tryptamine) have profound effects on gut microbial composition, microbial metabolism, the host's immune system, the host-microbiome interface, and host immune system-intestinal microbiota interactions. The aryl hydrocarbon receptor (AhR) mediates the regulation of intestinal immunity by Trp metabolites (as ligands of AhR), which is beneficial for immune homeostasis. Among Trp metabolites, AhR ligands consist of endogenous metabolites, including kynurenine, kynurenic acid, xanthurenic acid, and cinnabarinic acid, and bacterial metabolites, including indole, indole propionic acid, indole acetic acid, skatole, and tryptamine. Additional factors, such as aging, stress, probiotics, and diseases (spondyloarthritis, irritable bowel syndrome, inflammatory bowel disease, colorectal cancer), which are associated with variability in Trp metabolism, can influence Trp-microbiome-immune system interactions in the gut and also play roles in regulating gut immunity. This review clarifies how the gut microbiota regulates Trp metabolism and identifies the underlying molecular mechanisms of these interactions. Increased mechanistic insight into how the microbiota modulates the intestinal immune system through Trp metabolism may allow for the identification of innovative microbiota-based diagnostics, as well as appropriate nutritional supplementation of Trp to prevent or alleviate intestinal inflammation. Moreover, this review provides new insight regarding the influence of the gut microbiota on Trp metabolism. Additional comprehensive analyses of targeted Trp metabolites (including endogenous and bacterial metabolites) are essential for experimental preciseness, as the influence of the gut microbiota cannot be neglected, and may explain contradictory results in the literature.
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Affiliation(s)
- Jing Gao
- National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, China
- Key Laboratory of Agro-Ecology, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Kang Xu
- National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, China
- Key Laboratory of Agro-Ecology, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, China
| | - Hongnan Liu
- National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, China
- Key Laboratory of Agro-Ecology, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, China
| | - Gang Liu
- National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, China
- Key Laboratory of Agro-Ecology, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, China
| | - Miaomiao Bai
- National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, China
- Key Laboratory of Agro-Ecology, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, China
| | - Can Peng
- National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, China
- Key Laboratory of Agro-Ecology, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, China
| | - Tiejun Li
- National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, China
- Key Laboratory of Agro-Ecology, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, China
| | - Yulong Yin
- National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, China
- Key Laboratory of Agro-Ecology, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, China
- University of Chinese Academy of Sciences, Beijing, China
- College of Life Science, Hunan Normal University, Changsha, Hunan, China
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Wirthgen E, Hoeflich A, Rebl A, Günther J. Kynurenic Acid: The Janus-Faced Role of an Immunomodulatory Tryptophan Metabolite and Its Link to Pathological Conditions. Front Immunol 2018; 8:1957. [PMID: 29379504 PMCID: PMC5770815 DOI: 10.3389/fimmu.2017.01957] [Citation(s) in RCA: 251] [Impact Index Per Article: 35.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Accepted: 12/19/2017] [Indexed: 12/29/2022] Open
Abstract
Tryptophan metabolites are known to participate in the regulation of many cells of the immune system and are involved in various immune-mediated diseases and disorders. Kynurenic acid (KYNA) is a product of one branch of the kynurenine pathway of tryptophan metabolism. The influence of KYNA on important neurophysiological and neuropathological processes has been comprehensively documented. In recent years, the link of KYNA to the immune system, inflammation, and cancer has become more apparent. Given this connection, the anti-inflammatory and immunosuppressive functions of KYNA are of particular interest. These characteristics might allow KYNA to act as a "double-edged sword." The metabolite contributes to both the resolution of inflammation and the establishment of an immunosuppressive environment, which, for instance, allows for tumor immune escape. Our review provides a comprehensive update of the significant biological functions of KYNA and focuses on its immunomodulatory properties by signaling via G-protein-coupled receptor 35 (GPR35)- and aryl hydrocarbon receptor-mediated pathways. Furthermore, we discuss the role of KYNA-GPR35 interaction and microbiota associated KYNA metabolism for gut homeostasis.
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Affiliation(s)
- Elisa Wirthgen
- Institute for Genome Biology, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany
| | - Andreas Hoeflich
- Institute for Genome Biology, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany
| | - Alexander Rebl
- Institute for Genome Biology, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany
| | - Juliane Günther
- Institute for Genome Biology, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany
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Nikolaus S, Schulte B, Al-Massad N, Thieme F, Schulte DM, Bethge J, Rehman A, Tran F, Aden K, Häsler R, Moll N, Schütze G, Schwarz MJ, Waetzig GH, Rosenstiel P, Krawczak M, Szymczak S, Schreiber S. Increased Tryptophan Metabolism Is Associated With Activity of Inflammatory Bowel Diseases. Gastroenterology 2017; 153:1504-1516.e2. [PMID: 28827067 DOI: 10.1053/j.gastro.2017.08.028] [Citation(s) in RCA: 390] [Impact Index Per Article: 48.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 08/08/2017] [Accepted: 08/14/2017] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Administration of tryptophan and some of its metabolites reduces the severity of colitis in mice, whereas removing tryptophan from the diet increases susceptibility to colitis. Transfer of the intestinal microbiome transfers the colitogenic phenotype from tryptophan starved animals to normally nourished mice. We aimed to systematically evaluate serum levels of tryptophan and its metabolites in patients with inflammatory bowel diseases (IBD), and study their association with clinical and serologic features. METHODS We studied 535 consecutive patients with IBD (211 with ulcerative colitis [UC], 234 with Crohn's disease [CD]; 236 male), enrolled in Germany from August 2013 through April 2014 and followed until July 2016. Serum samples were collected from patients and 291 matched individuals without IBD (controls); levels of tryptophan were measured using high-performance liquid chromatography. Metabolites of tryptophan were measured in serum from 148 patients and 100 controls by mass spectrometry. We measured levels of interleukin 22 in serum from 28 patients by enzyme-linked immunosorbent assay. Paired stool and serum samples were collected from a subset of patients with active UC (n = 10) or CD (n = 8) to investigate associations between serum levels of tryptophan and composition of the fecal microbiota, analyzed by 16S ribosomal DNA amplicon sequencing. We used real-time polymerase chain reaction to measure levels of messenger RNAs in colonic biopsies from 60 patients with UC, 50 with CD, and 30 controls. We collected information on patients' disease activity scores, medications, laboratory assessments, and clinical examinations during recruitment and follow-up visits. RESULTS Serum levels of tryptophan were significantly lower in patients with IBD than in controls (P = 5.3 × 10-6) with a stronger reduction in patients with CD (vs control; P = 1.1 × 10-10) than UC (vs control; P = 2.8 × 10-3). We found a negative correlation between serum levels of tryptophan and disease activity or levels of C-reactive protein. Levels of messenger RNAs encoding tryptophan 2,3-dioxygenase-2 and solute carrier family 6 member 19 (also called B0AT1) were significantly decreased in colonic biopsies from patients with IBD compared with controls, whereas level of messenger RNA encoding indoleamine 2,3-dioxygenase-1 was significantly increased. The composition of the fecal microbiota associated with serum levels of tryptophan. Analysis of tryptophan metabolites revealed activation of the kynurenine pathway, based on high levels of quinolinic acid, in patients with IBD compared with controls. Serum concentration of interleukin 22 associated with disease activity in patients with IBD; there was an inverse association between levels of interleukin 22 and serum levels of tryptophan. CONCLUSIONS In an analysis of serum samples from more than 500 patients with IBD, we observed a negative correlation between serum levels of tryptophan and disease activity. Increased levels of tryptophan metabolites-especially of quinolinic acid-indicated a high activity of tryptophan degradation in patients with active IBD. Tryptophan deficiency could contribute to development of IBD or aggravate disease activity. Interventional clinical studies are needed to determine whether modification of intestinal tryptophan pathways affects the severity of IBD.
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Affiliation(s)
- Susanna Nikolaus
- Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Berenice Schulte
- Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Natalie Al-Massad
- Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Florian Thieme
- Institute of Clinical Chemistry, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Dominik M Schulte
- Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Johannes Bethge
- Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Ateequr Rehman
- Institute of Clinical Molecular Biology, University of Kiel, Germany
| | - Florian Tran
- Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany; Institute of Clinical Molecular Biology, University of Kiel, Germany
| | - Konrad Aden
- Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany; Institute of Clinical Molecular Biology, University of Kiel, Germany
| | - Robert Häsler
- Institute of Clinical Molecular Biology, University of Kiel, Germany
| | - Natalie Moll
- Institute of Laboratory Medicine, Medical Center of Ludwig Maximilian University, Munich, Germany
| | - Gregor Schütze
- Institute of Laboratory Medicine, Medical Center of Ludwig Maximilian University, Munich, Germany
| | - Markus J Schwarz
- Institute of Laboratory Medicine, Medical Center of Ludwig Maximilian University, Munich, Germany
| | | | - Philip Rosenstiel
- Institute of Clinical Molecular Biology, University of Kiel, Germany
| | - Michael Krawczak
- Institute of Medical Informatics and Statistics, University of Kiel, Germany
| | - Silke Szymczak
- Institute of Medical Informatics and Statistics, University of Kiel, Germany
| | - Stefan Schreiber
- Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany; Institute of Clinical Molecular Biology, University of Kiel, Germany.
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Kynurenine aminotransferase activity of Aro8/Aro9 engage tryptophan degradation by producing kynurenic acid in Saccharomyces cerevisiae. Sci Rep 2017; 7:12180. [PMID: 28939805 PMCID: PMC5610271 DOI: 10.1038/s41598-017-12392-6] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 09/07/2017] [Indexed: 12/12/2022] Open
Abstract
Kynurenic acid (KA) is a tryptophan (Trp) metabolite that is synthesised in a branch of kynurenine (KYN) pathway. KYN aminotransferase (KAT) catalyses deamination of KYN, yielding KA. Although KA synthesis is evolutionarily conserved from bacteria to humans, the cellular benefits of synthesising KA are unclear. In this study, we constructed a KAT-null yeast mutant defective in KA synthesis to clarify the cellular function of KA. Amino acid sequence analysis and LC/MS quantification of KA revealed that Aro8 and Aro9 are the major KATs. KA was significantly decreased in the aro8Δ aro9Δ double mutant. We found that aro8Δ aro9Δ cells did not exhibit obvious defects in growth or oxidative stress response when proper amounts of amino acids are supplied in the media. We further found that aro8Δ aro9Δ cells were sensitive to excess Trp. The Trp sensitivity was not rescued by addition of KA, suggesting that Trp sensitivity is not due to the loss of KA. In conclusion, we propose that KAT activity is required for detoxification of Trp by converting it to the less toxic KA.
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Gorska-Ponikowska M, Perricone U, Kuban-Jankowska A, Lo Bosco G, Barone G. 2-methoxyestradiol impacts on amino acids-mediated metabolic reprogramming in osteosarcoma cells by its interaction with NMDA receptor. J Cell Physiol 2017; 232:3030-3049. [PMID: 28262924 DOI: 10.1002/jcp.25888] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 03/02/2017] [Indexed: 12/28/2022]
Abstract
Deregulation of serine and glycine metabolism, have been identified to function as metabolic regulators in supporting tumor cell growth. The role of serine and glycine in regulation of cancer cell proliferation is complicated, dependent on concentrations of amino acids and tissue-specific. D-serine and glycine are coagonists of N-methyl-D-aspartate (NMDA) receptor subunit GRIN1. Importantly, NMDA receptors are widely expressed in cancer cells and play an important role in regulation of cell death, proliferation, and metabolism of numerous malignancies. The aim of the present work was to associate the metabolism of glycine and D-serine with the anticancer activity of 2-methoxyestradiol. 2-methoxyestradiol is a potent anticancer agent but also a physiological 17β- estradiol metabolite. In the study we have chosen two malignant cell lines expressing functional NMDA receptors, that is osteosarcoma 143B and breast cancer MCF7. We used MTS assay, migration assay, flow cytometric analyses, Western blotting and immunoprecipitation techniques as well as molecular modeling studies. We have demonstrated the extensive crosstalk between the deregulated metabolic network and cancer cell signaling. Herein, we observed an anticancer effect of high concentrations of glycine and D-serine in osteosarcoma cells. In contrast, the amino acids when used at low, physiological concentrations induced the proliferation and migration of osteosarcoma cells. Importantly, the pro-cancergogenic effects of both glycine and D-serine where abrogated by the usage of 2-methoxyestradiol at both physiological and pharmacological relevant concentrations. The obtained data confirmed that 2-methoxyestradiol may be a physiological anticancer molecule.
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Affiliation(s)
| | - Ugo Perricone
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, Università degli Studi di Palermo, Viale delle Scienze, Edificio 17, Palermo, Italy.,Fondazione Ri.MED, Palermo, Italy
| | | | - Giosuè Lo Bosco
- Dipartimento di Matematica e Informatica, Università degli Studi di Palermo, Palermo, Italy.,Istituto Euro Mediterraneo di Scienza e Tecnologia, Palermo, Italy
| | - Giampaolo Barone
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, Università degli Studi di Palermo, Viale delle Scienze, Edificio 17, Palermo, Italy
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Packiriswamy N, Coulson KF, Holcombe SJ, Sordillo LM. Oxidative stress-induced mitochondrial dysfunction in a normal colon epithelial cell line. World J Gastroenterol 2017; 23:3427-3439. [PMID: 28596679 PMCID: PMC5442079 DOI: 10.3748/wjg.v23.i19.3427] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 01/13/2017] [Accepted: 03/15/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To determine how a normal human colon cell line reacts to microbial challenge as a way to study oxidative stress-induced responses associated with inflammatory bowel disease.
METHODS Normal human colon epithelial cells (ATCC® CRL.1790™) were stimulated with either heat killed E. coli or heat killed murine cecal contents (HKC) and examined for several relevant biomarkers associated with inflammation and oxidative stress including cytokine production, mitochondrial autophagy and oxidant status. TNFα, IL-1β and IL-8 protein concentrations were measured within the supernatants. Fluorescent microscopy was performed to quantify the production of reactive oxygen species (ROS) using an oxidation responsive fluorogenic probe. Mitochondrial morphology and mitochondrial membrane potential was assessed by dual staining using COXIV antibody and a dye concentrating in active mitochondria. Mitochondrial ROS scavenger was used to determine the source of ROS in stimulated cells. Autophagy was detected by staining for the presence of autophagic vesicles. Positive controls for autophagy and ROS/RNS experiments were treated with rapamycin and chloroquine. Mitochondrial morphology, ROS production and autophagy microscopy experiments were analyzed using a custom acquisition and analysis microscopy software (ImageJ).
RESULTS Exposing CRL.1790 cells to microbial challenge stimulated cells to produce several relevant biomarkers associated with inflammation and oxidative stress. Heat killed cecal contents treatment induced a 10-12 fold increase in IL-8 production by CRL.1790 cells compared to unstimulated controls at 6 and 12 h (P < 0.001). Heat killed E. coli stimulation resulted in a 4-5 fold increase in IL-8 compared to the unstimulated control cells at each time point (P < 0.001). Both heat killed E. coli and HKC stimulated robust ROS production at 6 (P < 0.001), and 12 h (P < 0.01). Mitochondrial morphologic abnormalities were detected at 6 and 12 h based on reduced mitochondrial circularity and decreased mitochondrial membrane potential, P < 0.01. Microbial stimulation also induced significant autophagy at 6 and 12 h, P < 0.01. Lastly, blocking mitochondrial ROS generation using mitochondrial specific ROS scavenger reversed microbial challenge induced mitochondrial morphologic abnormalities and autophagy.
CONCLUSION The findings from this study suggest that CRL.1790 cells may be a useful alternative to other colon cancer cell lines in studying the mechanisms of oxidative stress events associated with intestinal inflammatory disorders.
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Hernandez-Martinez JM, Forrest CM, Darlington LG, Smith RA, Stone TW. Quinolinic acid induces neuritogenesis in SH-SY5Y neuroblastoma cells independently of NMDA receptor activation. Eur J Neurosci 2017; 45:700-711. [PMID: 27973747 DOI: 10.1111/ejn.13499] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Revised: 11/29/2016] [Accepted: 11/29/2016] [Indexed: 12/25/2022]
Abstract
Glutamate and nicotinamide adenine dinucleotide (NAD+ ) have been implicated in neuronal development and several types of cancer. The kynurenine pathway of tryptophan metabolism includes quinolinic acid (QA) which is both a selective agonist at N-methyl-D-aspartate (NMDA) receptors and also a precursor for the formation of NAD+ . The effect of QA on cell survival and differentiation has therefore been examined on SH-SY5Y human neuroblastoma cells. Retinoic acid (RA, 10 μm) induced differentiation of SH-SY5Y cells into a neuronal phenotype showing neurite growth. QA (50-150 nm) also caused a concentration-dependent increase in the neurite/soma ratio, indicating differentiation. Both RA and QA increased expression of the neuronal marker β3-tubulin in whole-cell homogenates and in the neuritic fraction assessed using a neurite outgrowth assay. Expression of the neuronal proliferation marker doublecortin revealed that, unlike RA, QA did not decrease the number of mitotic cells. QA-induced neuritogenesis coincided with an increase in the generation of reactive oxygen species. Neuritogenesis was prevented by diphenylene-iodonium (an inhibitor of NADPH oxidase) and superoxide dismutase, supporting the involvement of reactive oxygen species. NMDA itself did not promote neuritogenesis and the NMDA antagonist dizocilpine (MK-801) did not prevent quinolinate-induced neuritogenesis, indicating that the effects of QA were independent of NMDA receptors. Nicotinamide caused a significant increase in the neurite/soma ratio and the expression of β3-tubulin in the neuritic fraction. Taken together, these results suggest that QA induces neuritogenesis by promoting oxidizing conditions and affecting the availability of NAD+ , independently of NMDA receptors.
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Affiliation(s)
- Juan-Manuel Hernandez-Martinez
- Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, West Medical Building, Glasgow, G12 8QQ, UK
| | - Caroline M Forrest
- Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, West Medical Building, Glasgow, G12 8QQ, UK
| | | | - Robert A Smith
- Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, West Medical Building, Glasgow, G12 8QQ, UK
| | - Trevor W Stone
- Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, West Medical Building, Glasgow, G12 8QQ, UK
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Druzhyna N, Szczesny B, Olah G, Módis K, Asimakopoulou A, Pavlidou A, Szoleczky P, Gerö D, Yanagi K, Törö G, López-García I, Myrianthopoulos V, Mikros E, Zatarain JR, Chao C, Papapetropoulos A, Hellmich MR, Szabo C. Screening of a composite library of clinically used drugs and well-characterized pharmacological compounds for cystathionine β-synthase inhibition identifies benserazide as a drug potentially suitable for repurposing for the experimental therapy of colon cancer. Pharmacol Res 2016; 113:18-37. [PMID: 27521834 PMCID: PMC5107130 DOI: 10.1016/j.phrs.2016.08.016] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2016] [Revised: 08/08/2016] [Accepted: 08/09/2016] [Indexed: 01/23/2023]
Abstract
Cystathionine-β-synthase (CBS) has been recently identified as a drug target for several forms of cancer. Currently no potent and selective CBS inhibitors are available. Using a composite collection of 8871 clinically used drugs and well-annotated pharmacological compounds (including the LOPAC library, the FDA Approved Drug Library, the NIH Clinical Collection, the New Prestwick Chemical Library, the US Drug Collection, the International Drug Collection, the ‘Killer Plates’ collection and a small custom collection of PLP-dependent enzyme inhibitors), we conducted an in vitro screen in order to identify inhibitors for CBS using a primary 7-azido-4-methylcoumarin (AzMc) screen to detect CBS-derived hydrogen sulfide (H2S) production. Initial hits were subjected to counterscreens using the methylene blue assay (a secondary assay to measure H2S production) and were assessed for their ability to quench the H2S signal produced by the H2S donor compound GYY4137. Four compounds, hexachlorophene, tannic acid, aurintricarboxylic acid and benserazide showed concentration-dependent CBS inhibitory actions without scavenging H2S released from GYY4137, identifying them as direct CBS inhibitors. Hexachlorophene (IC50: ∼60 μM), tannic acid (IC50: ∼40 μM) and benserazide (IC50: ∼30 μM) were less potent CBS inhibitors than the two reference compounds AOAA (IC50: ∼3 μM) and NSC67078 (IC50: ∼1 μM), while aurintricarboxylic acid (IC50: ∼3 μM) was equipotent with AOAA. The second reference compound NSC67078 not only inhibited the CBS-induced AzMC fluorescence signal (IC50: ∼1 μM), but also inhibited with the GYY4137-induced AzMC fluorescence signal with (IC50 of ∼6 μM) indicative of scavenging/non-specific effects. Hexachlorophene (IC50: ∼6 μM), tannic acid (IC50: ∼20 μM), benserazide (IC50: ∼20 μM), and NSC67078 (IC50: ∼0.3 μM) inhibited HCT116 colon cancer cells proliferation with greater potency than AOAA (IC50: ∼300 μM). In contrast, although a CBS inhibitor in the cell-free assay, aurintricarboxylic acid failed to inhibit HCT116 proliferation at lower concentrations, and stimulated cell proliferation at 300 μM. Copper-containing compounds present in the libraries, were also found to be potent inhibitors of recombinant CBS; however this activity was due to the CBS inhibitory effect of copper ions themselves. However, copper ions, up to 300 μM, did not inhibit HCT116 cell proliferation. Benserazide was only a weak inhibitor of the activity of the other H2S-generating enzymes CSE and 3-MST activity (16% and 35% inhibition at 100 μM, respectively) in vitro. Benserazide suppressed HCT116 mitochondrial function and inhibited proliferation of the high CBS-expressing colon cancer cell line HT29, but not the low CBS-expressing line, LoVo. The major benserazide metabolite 2,3,4-trihydroxybenzylhydrazine also inhibited CBS activity and suppressed HCT116 cell proliferation in vitro. In an in vivo study of nude mice bearing human colon cancer cell xenografts, benserazide (50 mg/kg/day s.q.) prevented tumor growth. In silico docking simulations showed that benserazide binds in the active site of the enzyme and reacts with the PLP cofactor by forming reversible but kinetically stable Schiff base-like adducts with the formyl moiety of pyridoxal. We conclude that benserazide inhibits CBS activity and suppresses colon cancer cell proliferation and bioenergetics in vitro, and tumor growth in vivo. Further pharmacokinetic, pharmacodynamic and preclinical animal studies are necessary to evaluate the potential of repurposing benserazide for the treatment of colorectal cancers.
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Affiliation(s)
- Nadiya Druzhyna
- Department of Anesthesiology, The University of Texas Medical Branch, Galveston, TX, USA
| | - Bartosz Szczesny
- Department of Anesthesiology, The University of Texas Medical Branch, Galveston, TX, USA
| | - Gabor Olah
- Department of Anesthesiology, The University of Texas Medical Branch, Galveston, TX, USA
| | - Katalin Módis
- Department of Anesthesiology, The University of Texas Medical Branch, Galveston, TX, USA; Department of Surgery, The University of Texas Medical Branch, Galveston, TX, USA
| | - Antonia Asimakopoulou
- Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Greece; Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Greece
| | - Athanasia Pavlidou
- National and Kapodistrian University of Athens, School of Pharmacy, Athens, Greece
| | - Petra Szoleczky
- Department of Anesthesiology, The University of Texas Medical Branch, Galveston, TX, USA
| | - Domokos Gerö
- Department of Anesthesiology, The University of Texas Medical Branch, Galveston, TX, USA
| | - Kazunori Yanagi
- Department of Anesthesiology, The University of Texas Medical Branch, Galveston, TX, USA
| | - Gabor Törö
- Department of Anesthesiology, The University of Texas Medical Branch, Galveston, TX, USA
| | - Isabel López-García
- Department of Anesthesiology, The University of Texas Medical Branch, Galveston, TX, USA
| | | | - Emmanuel Mikros
- National and Kapodistrian University of Athens, School of Pharmacy, Athens, Greece
| | - John R Zatarain
- Department of Surgery, The University of Texas Medical Branch, Galveston, TX, USA
| | - Celia Chao
- Department of Surgery, The University of Texas Medical Branch, Galveston, TX, USA
| | - Andreas Papapetropoulos
- Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Greece; National and Kapodistrian University of Athens, School of Pharmacy, Athens, Greece
| | - Mark R Hellmich
- Department of Surgery, The University of Texas Medical Branch, Galveston, TX, USA; CBS Therapeutics Inc., Galveston, TX, USA
| | - Csaba Szabo
- Department of Anesthesiology, The University of Texas Medical Branch, Galveston, TX, USA; CBS Therapeutics Inc., Galveston, TX, USA.
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Langner E, Lemieszek MK, Kwiecień JM, Rajtar G, Rzeski W, Turski WA. Kynurenic Acid Induces Impairment of Oligodendrocyte Viability: On the Role of Glutamatergic Mechanisms. Neurochem Res 2016; 42:838-845. [PMID: 27444613 PMCID: PMC5357470 DOI: 10.1007/s11064-016-2009-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Revised: 07/12/2016] [Accepted: 07/15/2016] [Indexed: 01/26/2023]
Abstract
Kynurenic acid (KYNA) is an end stage product of tryptophan metabolism with a variety of functions in the human body, both in the central nervous system (CNS) and in other organs. Although its activity in the human brain has been widely studied and effects on neural cells were emphasized, the effect of KYNA on oligodendroglial cells remains unknown. Present study aims at describing the activity of high concentration of KYNA in OLN-93 cells. The inhibition of OLN-93 oligodendrocytes viability by KYNA in a medium with reduced serum concentration has been demonstrated. Although decreased metabolic activity of KYNA treated OLN-93 cells was shown, the cells proliferation was not altered. KYNA treatment did not alter morphology as well as expression level of cell cycle and proliferation regulating proteins. Furthermore, glutamate receptor antagonists and agonists did not alter the inhibitory effect of KYNA on viability of OLN-93 oligodendrocytes. This study contributes to the elucidation of effects of KYNA on oligodendrocytes in vitro, yet further analyses are necessary to explain the mechanisms behind the damage and loss of myelin sheaths.
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Affiliation(s)
- Ewa Langner
- Department of Medical Biology, Institute of Rural Health, Lublin, Poland.,Department of Pharmacology, Medical University, Lublin, Poland
| | - Marta K Lemieszek
- Department of Medical Biology, Institute of Rural Health, Lublin, Poland
| | - Jacek M Kwiecień
- Department of Pathology and Molecular Medicine, M. deGroote School of Medicine, McMaster University, Hamilton, Canada.,Department of Clinical Pathomorphology, Medical University, Lublin, Poland
| | - Grażyna Rajtar
- Department of Pharmacology, Medical University, Lublin, Poland
| | - Wojciech Rzeski
- Department of Medical Biology, Institute of Rural Health, Lublin, Poland.,Department of Virology and Immunology, Institute of Microbiology and Biotechnology, Maria Curie-Sklodowska University, Lublin, Poland
| | - Waldemar A Turski
- Department of Experimental and Clinical Pharmacology, Medical University, Lublin, Poland.
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