Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation

Adam, Isabell; Dewi, Dyah Laksmi; Sadik, Ahmed; Mohapatra, Soumya R.; Berdel, Bianca; Keil, Melanie; Sonner, Jana K.; Thedieck, Kathrin; Rose, Adam J.; Platten, Michael; Heiland, Ines; Trump, Saskia; Opitz, Christiane A.

doi:10.1080/2162402x.2018.1486353

Cited by 52 publications

(48 citation statements)

References 54 publications

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“…Upregulation of IDO1 was high on protein levels in HROG05 cells and marginal in HROG63 (Figure 3B). TDO2 and KYAT3 were suppressed upon IFNγ stimulation in three of five samples and hardly detectable in one cell line, supporting data from a recent publication (38). KYNU was not affected by IFNγ stimulation (Figure 3A).…”

Section: Basal Ido1 and Related Genes In Gbm And Hnscc Cell Linessupporting

confidence: 87%

“…Our results confirm these data, and in addition, we were able to demonstrate that IFNγ stimulation in combination with TMZ stimulated KYN and KYNA production and TRP catabolism in GBM cell cultures. The increase in TRP catabolism and KYN production (KYN/TRP ratio) is widely used as indirect indicator of the cumulative activities of TDO2, IDO1, and IDO-2 (38,46). The KP in brain tumors is likely triggered by IFNγ from immediate surrounding tissue (29,47,48).…”

Section: Discussionmentioning

confidence: 99%

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Activation of the Kynurenine Pathway in Human Malignancies Can Be Suppressed by the Cyclin-Dependent Kinase Inhibitor Dinaciclib

et al. 2020

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Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO2) are the key enzymes of tryptophan (TRP) metabolism in the kynurenine pathway (KP). Both enzymes function as indicators of immunosuppression and poor survival in cancer patients. Direct or indirect targeting of either of these substances seems thus reasonable to improve therapy options for patients. In this study, glioblastoma multiforme (GBM) as well as head and neck squamous cell carcinomas (HNSCC) were examined because of their different mechanisms of spontaneous and treatment-induced immune escape. Effects on gene expression and protein levels were examined. Accompanying assessment of TRP metabolites from treated GBM cell culture supernatants was conducted. Our results show a heterogeneous and inversely correlated expression profile of TRP-metabolizing genes among GBM and HNSCC cells, with low, but inducible IDO1 expression upon IFNγ treatment. TDO2 expression was higher in GBM cells, while genes encoding kynurenine aminotransferases were mainly confined to HNSCC cells. These data indicate that the KP is active in both entities, with however different enzymes involved in TRP catabolism. Upon treatment with Temozolomide, the standard of care for GBM patients, IDO1 was upregulated. Comparable, although less pronounced effects were seen in HNSCC upon Cetuximab and conventional drugs (i.e., 5-fluorouracil, Gemcitabine). Here, IDO1 and additional genes of the KP (KYAT1, KYAT2, and KMO) were induced. Vice versa, the novel yet experimental cyclin-dependent kinase inhibitor Dinaciclib suppressed KP in both entities. Our comprehensive data imply inhibition of the TRP catabolism by Dinaciclib, while conventional chemotherapeutics tend to activate this pathway. These data point to limitations of conventional therapy and highlight the potential of targeted therapies to interfere with the cells' metabolism more than anticipated.

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Section: Basal Ido1 and Related Genes In Gbm And Hnscc Cell Linessupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Activation of the Kynurenine Pathway in Human Malignancies Can Be Suppressed by the Cyclin-Dependent Kinase Inhibitor Dinaciclib

et al. 2020

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“…On the other hand, the BLIMP1 protein binds to the IDO promoter, repressing its expression (64). The tryptophan degradation also modifies the expression of SLC7A5 (65) and WARS during this process in cancer cells (66) and ASCs (67). Regarding cancer cells, the prognostic of diffuse large B-cell lymphoma, mainly composed by ASCs, and its outcome for a patients have been strongly connected to the IDO expression and the presence of determined serum kynurenine concentrations (68)(69)(70)(71).…”

Section: Discussionmentioning

confidence: 99%

Flavivirus-Mediating B Cell Differentiation Into Antibody-Secreting Cells in Humans Is Associated With the Activation of the Tryptophan Metabolism

et al. 2020

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Patients infected with the Dengue virus (DENV) often present with a massive generation of DENV-specific antibody-secreting cells (ASCs) in the blood. In some cases, these ASCs represent more than 50% of the circulating B cells, a higher magnitude than those induced by other infections, vaccinations, and plasma cell lymphomas. However, it remains unclear how the DENV infection elicits this colossal response. To address this issue, we utilised an in vitro strategy to induce human PBMCs of healthy individuals incubated with DENV particles (DENV4 TVP/360) to differentiate into ASCs. As controls, PBMCs were incubated with a mitogen cocktail or supernatants of uninfected C6/36 cells (mock). The ASC phenotype and function were increasingly detected in the DENV and mitogen-cultured PBMCs as compared to mock-treated cells. In contrast to the in vivo condition, secreted IgG derived from the PBMC-DENV culture was not DENV-specific. Lower ASC numbers were observed when inactivated viral particles or purified B cells were added to the cultures. The physical contact was essential between B cells and the remaining PBMCs for the DENV-mediated ASC response. Considering the evidence for the activation of the tryptophan metabolism detected in the serum of Dengue patients, we assessed its relevance in the DENV-mediated ASC differentiation. For this, tryptophan and its respective metabolites were quantified in the supernatants of cell cultures through mass spectrophotometry. Tryptophan depletion and kynurenine accumulation were found in the supernatants of PBMC-DENV cultures, which presented enhanced detection of indoleamine 2,3-dioxygenase 1 and 2 transcripts as compared to controls. In PBMC-DENV cultures, tryptophan and kynurenine levels strongly correlated to the respective ASC numbers, while the kynurenine levels were directly proportional to the secreted IgG titers. Contrastingly, PBMCs incubated with Zika or attenuated Bonezi et al. Dengue-Mediated Antibody-Secreting Cell DifferentiationYellow Fever viruses showed no correlation between their kynurenine concentrations and ASC numbers. Therefore, our data revealed the existence of distinct pathways for the DENV-mediated ASC differentiation and suggest the involvement of the tryptophan metabolism in this cellular process triggered by flavivirus infections.

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“…Additionally, tumor cells might enhance their own IDO activity via an autocrine AhR-IL-6-STAT3 signaling loop (148), thereby suppressing T-cell proliferation. Upregulation of the tryptophanyl-tRNA synthetase WARS may protect Trp-degrading cancer cells from excessive intracellular Trp depletion via IFNγ and/or GCN2signaling (149).…”

Section: Tryptophan Breakdown Via the Kynurenine Pathway Modulates Immentioning

confidence: 99%

Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer

et al. 2020

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Many patients with cancer suffer from anemia, depression, and an impaired quality of life (QoL). These patients often also show decreased plasma tryptophan levels and increased kynurenine concentrations in parallel with elevated concentrations of Th1 type immune activation marker neopterin. In the course of anti-tumor immune response, the pro-inflammatory cytokine interferon gamma (IFN-γ) induces both, the enzyme indoleamine 2,3-dioxygenase (IDO) to degrade tryptophan and the enzyme GTP-cyclohydrolase I to form neopterin. High neopterin concentrations as well as an increased kynurenine to tryptophan ratio (Kyn/Trp) in the blood of cancer patients are predictive for a worse outcome. Inflammation-mediated tryptophan catabolism along the kynurenine pathway is related to fatigue and anemia as well as to depression and a decreased QoL in patients with solid tumors. In fact, enhanced tryptophan breakdown might greatly contribute to the development of anemia, fatigue, and depression in cancer patients. IDO activation and stimulation of the kynurenine pathway exert immune regulatory mechanisms, which may impair anti-tumor immune responses. In addition, tumor cells can degrade tryptophan to weaken immune responses directed against them. High IDO expression in the tumor tissue is associated with a poor prognosis of patients. The efficiency of IDO-inhibitors to inhibit cancer progression is currently tested in combination with established chemotherapies and with immune checkpoint inhibitors. Inflammation-mediated tryptophan catabolism and its possible influence on the development and persistence of anemia, fatigue, and depression in cancer patients are discussed.

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Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation

Cited by 52 publications

References 54 publications

Activation of the Kynurenine Pathway in Human Malignancies Can Be Suppressed by the Cyclin-Dependent Kinase Inhibitor Dinaciclib

Activation of the Kynurenine Pathway in Human Malignancies Can Be Suppressed by the Cyclin-Dependent Kinase Inhibitor Dinaciclib

Flavivirus-Mediating B Cell Differentiation Into Antibody-Secreting Cells in Humans Is Associated With the Activation of the Tryptophan Metabolism

Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer

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