Dysregulation at multiple points of the kynurenine pathway is a ubiquitous feature of renal cancer: implications for tumour immune evasion.

3-Hydroxyanthranilate 3,4-Dioxygenase / genetics Carcinoma, Renal Cell / genetics Cell Line, Tumor Cytokines / genetics Gene Expression Profiling Gene Expression Regulation, Neoplastic / genetics Humans Kynurenine / genetics Kynurenine 3-Monooxygenase / genetics Metabolic Networks and Pathways / genetics Nicotinamide Phosphoribosyltransferase / genetics Proteomics Tumor Escape / genetics

Journal

British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635

Informations de publication

Date de publication:
07 2020
Historique:
received: 14 11 2019
accepted: 15 04 2020
pubmed: 12 5 2020
medline: 20 2 2021
entrez: 12 5 2020
Statut: ppublish

Résumé

Indoleamine 2,3-dioxygenase (IDO), the first step in the kynurenine pathway (KP), is upregulated in some cancers and represents an attractive therapeutic target given its role in tumour immune evasion. However, the recent failure of an IDO inhibitor in a late phase trial raises questions about this strategy. Matched renal cell carcinoma (RCC) and normal kidney tissues were subject to proteomic profiling. Tissue immunohistochemistry and gene expression data were used to validate findings. Phenotypic effects of loss/gain of expression were examined in vitro. Quinolate phosphoribosyltransferase (QPRT), the final and rate-limiting enzyme in the KP, was identified as being downregulated in RCC. Loss of QPRT expression led to increased potential for anchorage-independent growth. Gene expression, mass spectrometry (clear cell and chromophobe RCC) and tissue immunohistochemistry (clear cell, papillary and chromophobe), confirmed loss or decreased expression of QPRT and showed downregulation of other KP enzymes, including kynurenine 3-monoxygenase (KMO) and 3-hydroxyanthranilate-3,4-dioxygenase (HAAO), with a concomitant maintenance or upregulation of nicotinamide phosphoribosyltransferase (NAMPT), the key enzyme in the NAD+ salvage pathway. Widespread dysregulation of the KP is common in RCC and is likely to contribute to tumour immune evasion, carrying implications for effective therapeutic targeting of this critical pathway.

Sections du résumé

BACKGROUND
Indoleamine 2,3-dioxygenase (IDO), the first step in the kynurenine pathway (KP), is upregulated in some cancers and represents an attractive therapeutic target given its role in tumour immune evasion. However, the recent failure of an IDO inhibitor in a late phase trial raises questions about this strategy.
METHODS
Matched renal cell carcinoma (RCC) and normal kidney tissues were subject to proteomic profiling. Tissue immunohistochemistry and gene expression data were used to validate findings. Phenotypic effects of loss/gain of expression were examined in vitro.
RESULTS
Quinolate phosphoribosyltransferase (QPRT), the final and rate-limiting enzyme in the KP, was identified as being downregulated in RCC. Loss of QPRT expression led to increased potential for anchorage-independent growth. Gene expression, mass spectrometry (clear cell and chromophobe RCC) and tissue immunohistochemistry (clear cell, papillary and chromophobe), confirmed loss or decreased expression of QPRT and showed downregulation of other KP enzymes, including kynurenine 3-monoxygenase (KMO) and 3-hydroxyanthranilate-3,4-dioxygenase (HAAO), with a concomitant maintenance or upregulation of nicotinamide phosphoribosyltransferase (NAMPT), the key enzyme in the NAD+ salvage pathway.
CONCLUSIONS
Widespread dysregulation of the KP is common in RCC and is likely to contribute to tumour immune evasion, carrying implications for effective therapeutic targeting of this critical pathway.

Identifiants

DOI: 10.1038/s41416-020-0874-y PMID: 32390008 PMC: PMC7341846
pubmed: 32390008
doi: 10.1038/s41416-020-0874-y
pii: 10.1038/s41416-020-0874-y
pmc: PMC7341846
doi:

Substances chimiques

Cytokines 0
Kynurenine 343-65-7
3-Hydroxyanthranilate 3,4-Dioxygenase EC 1.13.11.6
Kynurenine 3-Monooxygenase EC 1.14.13.9
Nicotinamide Phosphoribosyltransferase EC 2.4.2.12
nicotinamide phosphoribosyltransferase, human EC 2.4.2.12

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

137-147

Subventions

Organisme : Cancer Research UK (CRUK)
ID : C8175/A7672

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Auteurs

Nick Hornigold (N)

Clinical and Biomedical Proteomics Group, University of Leeds, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Karen R Dunn (KR)

Clinical and Biomedical Proteomics Group, University of Leeds, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Rachel A Craven (RA)

Clinical and Biomedical Proteomics Group, University of Leeds, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Alexandre Zougman (A)

Clinical and Biomedical Proteomics Group, University of Leeds, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK.
Leeds Institute of Medical Research at St James's, University of Leeds, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Sebastian Trainor (S)

Clinical and Biomedical Proteomics Group, University of Leeds, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Rebecca Shreeve (R)

Clinical and Biomedical Proteomics Group, University of Leeds, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Joanne Brown (J)

Clinical and Biomedical Proteomics Group, University of Leeds, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK.
Leeds Institute of Medical Research at St James's, University of Leeds, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Helen Sewell (H)

Clinical and Biomedical Proteomics Group, University of Leeds, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Michael Shires (M)

Leeds Institute of Medical Research at St James's, University of Leeds, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Margaret Knowles (M)

Molecular Genetics Group, University of Leeds, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Tsutomu Fukuwatari (T)

Department of Nutrition, The University of Shiga Prefecture, 2500 Hassaka, Hikone, 5228533, Japan.

Eamonn R Maher (ER)

Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.

Julie Burns (J)

Molecular Genetics Group, University of Leeds, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Selina Bhattarai (S)

Department of Pathology, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Mini Menon (M)

Department of Pathology, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Alvis Brazma (A)

European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, CB10 1SD, UK.

Ghislaine Scelo (G)

International Agency for Research on Cancer (IARC), Genetic Epidemiology Group, 150 cours Albert Thomas, 69372, Lyon, France.

Lara Feulner (L)

McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada.

Yasser Riazalhosseini (Y)

McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada.

Mark Lathrop (M)

McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada.

Adrian Harris (A)

Cancer Research UK Clinical Centre, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK.

Peter J Selby (PJ)

Clinical and Biomedical Proteomics Group, University of Leeds, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Rosamonde E Banks (RE)

Clinical and Biomedical Proteomics Group, University of Leeds, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK.
Leeds Institute of Medical Research at St James's, University of Leeds, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Naveen S Vasudev (NS)

Clinical and Biomedical Proteomics Group, University of Leeds, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK. n.vasudev@leeds.ac.uk.
Leeds Institute of Medical Research at St James's, University of Leeds, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK. n.vasudev@leeds.ac.uk.
ORCID: 0000-0001-8470-7481

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Classifications MeSH

questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Oxidoreductases › Oxygénases › Dioxygenases › 3-Hydroxyanthranilate 3,4-dioxygenase › Dysregulation at multiple points of the...
questionsmedicales.fr › Maladies urogénitales › Maladies urologiques › Tumeurs urologiques › Tumeurs du rein › Néphrocarcinome › Dysregulation at multiple points of the...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Dysregulation at multiple points of the...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Dysregulation at multiple points of the...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de profil d'expression de gènes › Dysregulation at multiple points of the...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › Dysregulation at multiple points of the...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Dysregulation at multiple points of the...
questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › Cynurénine › Dysregulation at multiple points of the...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Oxidoreductases › Oxygénases › Mixed function oxygenases › Kynurenine 3-monooxygenase › Dysregulation at multiple points of the...
questionsmedicales.fr › Métabolisme › Voies et réseaux métaboliques › Dysregulation at multiple points of the...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Glycosyltransferase › Pentosyltransferases › Nicotinamide phosphoribosyltransferase › Dysregulation at multiple points of the...
questionsmedicales.fr › Disciplines des sciences naturelles › Chimie › Biochimie › Protéomique › Dysregulation at multiple points of the...
questionsmedicales.fr › Phénomènes du système immunitaire › Échappement de la tumeur à la surveillance immunitaire › Dysregulation at multiple points of the...