ArticleOncoimmunology
Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation.
Article in Oncoimmunology. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 60 citations in OpenAlex.
- Tryptophan metabolism in tumor microenvironment and therapeutic implications.Journal of advanced research · 2026Review
- Long-Chain S-Acylation Is a Key Modulator During the Macrophage Inflammatory Response.Molecular & cellular proteomics : MCP · 2026Article
- Amino Acids as Targets for Immunotherapy against Solid Tumors.Cell biochemistry and biophysics · 2026Review
- Aminoacyl-tRNA synthetases in tumor immunity: canonical translation, source-resolved immune circuits and therapeutic opportunities.Frontiers in immunology · 2026Review
- Depletion of tryptophanyl-tRNA synthetase and tryptophan accumulation triggers p53-dependent apoptosis.Cell death discovery · 2025Article
- AI-Assisted Identification of Primary and Secondary Metabolomic Markers for Postoperative Delirium.International journal of molecular sciences · 2024Article
- Multifaceted role of GCN2 in tumor adaptation and therapeutic targeting.Translational oncology · 2024Review
- The high-affinity tryptophan uptake transport system in human cells.Biochemical Society transactions · 2024Review
- Tryptophan catabolism via the kynurenine pathway regulates infection and inflammation: from mechanisms to biomarkers and therapies.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2024Review
- Size-exclusion chromatography combined with DIA-MS enables deep proteome profiling of extracellular vesicles from melanoma plasma and serum.Cellular and molecular life sciences : CMLS · 2024Article
- Targeting amino acid-metabolizing enzymes for cancer immunotherapy.Frontiers in immunology · 2024Review
- Plasma proteome of growing tumors.Scientific reports · 2023Article
- Immune regulation through tryptophan metabolism.Experimental & molecular medicine · 2023Review
- Tryptophan depletion sensitizes the AHR pathway by increasing AHR expression and GCN2/LAT1-mediated kynurenine uptake, and potentiates induction of regulatory T lymphocytes.Journal for immunotherapy of cancer · 2023Article
- In Situ Imaging of O-Linked β-N-Acetylglucosamine Using On-Tissue Hydrolysis and MALDI Mass Spectrometry.Cancers · 2023Article
- Dependence on MUC1-C in Progression of Neuroendocrine Prostate Cancer.International journal of molecular sciences · 2023Review
- Quantitative Proteomics of Polarised Macrophages Derived from Induced Pluripotent Stem Cells.Biomedicines · 2022Article
- The pathophyiological role of aminoacyl-tRNA synthetases in digestive system diseases.Frontiers in physiology · 2022Review
- MUC1-C integrates type II interferon and chromatin remodeling pathways in immunosuppression of prostate cancer.Oncoimmunology · 2022Article
- The COVIDome Explorer researcher portal.Cell reports · 2021Article
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Authors and funding
14 authors at 5 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Tryptophan (Trp) metabolism is an important target in immuno-oncology as it represents a powerful immunosuppressive mechanism hijacked by tumors for protection against immune destruction. However, it remains unclear how tumor cells can proliferate while degrading the essential amino acid Trp. Trp is incorporated into proteins after it is attached to its tRNA by tryptophanyl-tRNA synthestases. As the tryptophanyl-tRNA synthestases compete for Trp with the Trp-catabolizing enzymes, the balance between these enzymes will determine whether Trp is used for protein synthesis or is degraded. In human cancers expression of the Trp-degrading enzymes indoleamine-2,3-dioxygenase-1 (IDO1) and tryptophan-2,3-dioxygenase (TDO2) was positively associated with the expression of the tryptophanyl-tRNA synthestase WARS. One mechanism underlying the association between IDO1 and WARS identified in this study is their joint induction by IFNγ released from tumor-infiltrating T cells. Moreover, we show here that IDO1- and TDO2-mediated Trp deprivation upregulates WARS expression by activating the general control non-derepressible-2 (GCN2) kinase, leading to phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α) and induction of activating transcription factor 4 (ATF4). Trp deprivation induced cytoplasmic WARS expression but did not increase nuclear or extracellular WARS levels. GCN2 protected the cells against the effects of Trp starvation and enabled them to quickly make use of Trp for proliferation once it was replenished. Computational modeling of Trp metabolism revealed that Trp deficiency shifted Trp flux towards WARS and protein synthesis. Our data therefore suggest that the upregulation of WARS via IFNγ and/or GCN2-peIF2α-ATF4 signaling protects Trp-degrading cancer cells from excessive intracellular Trp depletion.
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