Dysregulation at multiple points of the kynurenine pathway is a ubiquitous feature of renal cancer: implications for tumour immune evasion
Autor: | Helen Sewell, Nick Hornigold, Naveen S. Vasudev, Eamonn R. Maher, Margaret A. Knowles, Mini Menon, Tsutomu Fukuwatari, Yasser Riazalhosseini, Alvis Brazma, Karen R. Dunn, Selina Bhattarai, Rachel A. Craven, Rosamonde E. Banks, Adrian L. Harris, Julie E. Burns, Alexandre Zougman, Peter Selby, Lara Feulner, Ghislaine Scelo, Michael Shires, Sebastian Trainor, Rebecca Shreeve, Joanne Brown, Mark Lathrop |
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Přispěvatelé: | Vasudev, Naveen S [0000-0001-8470-7481], Apollo - University of Cambridge Repository, Vasudev, Naveen S. [0000-0001-8470-7481] |
Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
Proteomics
Cancer Research Kynurenine pathway 631/67/589/1588/1351 Nicotinamide phosphoribosyltransferase Chromophobe cell Biology 631/67/2327 Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Immune system Kynurenine 3-Monooxygenase Downregulation and upregulation Renal cell carcinoma Cell Line Tumor medicine Humans 3-Hydroxyanthranilate 3 4-Dioxygenase Nicotinamide Phosphoribosyltransferase Carcinoma Renal Cell Kynurenine 030304 developmental biology 0303 health sciences Gene Expression Profiling medicine.disease Cancer metabolism Gene Expression Regulation Neoplastic Oncology chemistry 030220 oncology & carcinogenesis biology.protein Cancer research Phosphoribosyltransferase Cytokines Tumor Escape Metabolic Networks and Pathways |
Zdroj: | British Journal of Cancer |
ISSN: | 1532-1827 0007-0920 |
Popis: | Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199 Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272 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 |
Databáze: | OpenAIRE |
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