The Kynurenine Pathway and Cancer: Why Keep It Simple When You Can Make It Complicated

Gouasmi, Roumaïssa; Ferraro‐Peyret, Carole; Nancey, Stéphane; Coste, Isabelle; Renno, Toufic; Chaveroux, Cédric; Aznar, Nicolas; Ansieau, Stéphane

doi:10.3390/cancers14112793

Cited by 34 publications

(33 citation statements)

References 104 publications

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“…However, the exact mechanisms of this potential therapeutic pathway in HCC cells remain unclear. Hepatic cell lines provide the best available environment to evaluate the exact correlation between Kyneurine and its metabolites in HCC patients [ 11 ]. However, due to their high cost, invasiveness, and the diminished activity of numerous important enzymes, immortalized hepatic cell lines are frequently utilized instead of liver biopsies in much research.…”

Section: Introductionmentioning

confidence: 99%

Kynurenine Is the Main Metabolite of Tryptophan Degradation by Tryptophan 2,3-Dioxygenase in HepaRG Tumor Cells

Oweira

Lahdou

Mehrle

et al. 2022

JCM

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There are two main enzymes that convert tryptophan (Trp) to kynurenine (Kyn): tryptophan-2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO). Kyn accumulation can promote immunosuppression in certain cancers. In this study, we investigated Trp degradation to Kyn by IDO and TDO in primary human hepatocytes (PHH) and tumoral HepG2 cells. To quantify Trp-degradation and Kyn-accumulation, using reversed-phase high-pressure liquid chromatography, the levels of Trp and Kyn were determined in the culture media of PHH and HepG2 cells. The role of IDO in Trp metabolism was investigated by activating IDO with IFN-γ and inhibiting IDO with 1-methyl-tryptophan (1-DL-MT). The role of TDO was investigated using one of two TDO inhibitors: 680C91 or LM10. Real-time PCR was used to measure TDO and IDO expression. Trp was degraded in both PHH and HepG2 cells, but degradation was higher in PHH cells. However, Kyn accumulation was higher in the supernatants of HepG2 cells. Stimulating IDO with IFN-γ did not significantly affect Trp degradation and Kyn accumulation, even though it strongly upregulated IDO expression. Inhibiting IDO with 1-DL-MT also had no effect on Trp degradation. In contrast, inhibiting TDO with 680C91 or LM10 significantly reduced Trp degradation. The expression of TDO but not of IDO correlated positively with Kyn accumulation in the HepG2 cell culture media. Furthermore, TDO degraded L-Trp but not D-Trp in HepG2 cells. Kyn is the main metabolite of Trp degradation by TDO in HepG2 cells. The accumulation of Kyn in HepG2 cells could be a key mechanism for tumor immune resistance. Two TDO inhibitors, 680C91 and LM10, could be useful in immunotherapy for liver cancers.

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Section: Introductionmentioning

confidence: 99%

Kynurenine Is the Main Metabolite of Tryptophan Degradation by Tryptophan 2,3-Dioxygenase in HepaRG Tumor Cells

Oweira

Lahdou

Mehrle

et al. 2022

JCM

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“…Our initial analysis revealed significantly elevated levels of metabolites involved in Trp metabolism in breast tumor tissues, including KYN, compared to normal breast tissues. Interestingly, KYN is regarded as an inflammatory marker, which is a common characteristic in cancer [ 17 , 18 ]. While KYN can function to modulate the inflammatory immune response in normal tissues, activity of this pathway in tumor cells tends to be overexpressed and can lead to the depletion of tryptophan in the microenvironment, thereby suppressing T-cell mediated immune response [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Metabolome of Breast Tissues from Non-Hispanic Black and Non-Hispanic White Women Reveals Correlations between Microbial Dysbiosis and Enhanced Lipid Metabolism Pathways in Triple-Negative Breast Tumors

Smith

Cao

et al. 2022

Cancers

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Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer that is non-responsive to hormonal therapies and disproportionately impact women of African ancestry. We previously showed that TN breast tumors have a distinct microbial signature that differs from less aggressive breast tumor subtypes and normal breast tissues. However, it is unknown whether these differences in breast tumor microbiota may be driven by alterations in microbial metabolites, leading to potentially protective or pathogenic consequences. The goal of this global metabolomic profiling study was to investigate alterations in microbial metabolism pathways in normal and breast tumor tissues, including TNBC, of non-Hispanic black (NHB) and non-Hispanic white (NHW) women. In this study, we profiled the microbiome (16S rRNA) from breast tumor tissues and analyzed 984 metabolites from a total of 51 NHB and NHW women. Breast tumor tissues were collected from 15 patients with TNBC, 12 patients with less aggressive luminal A-type (Luminal) breast cancer, and 24 healthy controls for comparison using UHPLC-tandem mass spectrometry. Principal component analysis and hierarchical clustering of the global metabolomic profiling data revealed separation between metabolic signatures of normal and breast tumor tissues. Random forest analysis revealed a unique biochemical signature associated with elevated lipid metabolites and lower levels of microbial-derived metabolites important in controlling inflammation and immune responses in breast tumor tissues. Significant relationships between the breast microbiome and the metabolome, particularly lipid metabolism, were observed in TNBC tissues. Further investigations to determine whether alterations in sphingolipid, phospholipid, ceramide, amino acid, and energy metabolism pathways modulate Fusobacterium and Tenericutes abundance and composition to alter host metabolism in TNBC are necessary to help us understand the risk and underlying mechanisms and to identify potential microbial-based targets.

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“…For example, our network analysis on the RNA-Seq data from IRF7 wild-type and knockdown cells identified IDO1 as a druggable target amongst Type 1 interferon response genes. IDO1 as a metabolic enzyme has important cancer cell-intrinsic and extrinsic effects arising from the production of kynurenine from tryptophan [37]. Cancer-cell intrinsic effects of IDO1 centre on the DNA repair capacity of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

IRF7 impacts on prostate cancer cell survival in response to radiation

Pickard

Amoroso

McCulloch

et al. 2022

Preprint

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Understanding the impact of radiotherapy on the evolution of treatment resistant prostate cancer is critical for selecting effective treatment combinations. Whilst activation of Type 1 interferon signalling is a hallmark of how cells respond to viral infection, in cancer cells, multiple stresses are known to activate this same response. In this study we have evaluated for the first time the changes in the interferon response induced by culturing prostate cancer cells under sphere-forming conditions and following irradiation. We report a conserved upregulated transcript profile for both conditions that is strongly associated with therapeutic resistance and cell survival in vitro and in vivo. The profile includes and is regulated by the Type 1 interferon master regulator IRF7 which, when depleted, delays tumour re-growth following irradiation. We immuno-stained two independent prostate cohorts for IRF7 and found that increased expression, particularly in cases with low PTEN expression, correlated with poor prognosis. To more comprehensively characterise the impact of IRF7 and radiation on cells, RNA-Seq was performed on IRF7 knockdown cells at different radiation doses. We identified a number of biological processes that were IRF7-dependent, including the formation of stem-like cell populations and also therapeutic vulnerabilities. For example, irradiation sensitised surviving cells to either a combination of an IKKε/TBK1 and a MEK inhibitor or treatment with an inhibitor of IDO1, an IRF7-dependent gene. Translationally our work suggests that IRF7 expression can be used to stratify patients who may not benefit from receiving radiotherapy alone but rather may benefit from treatment combinations. In two cohorts treated with radical intent, strong IRF7 staining was associated with disease-specific death implicating this pathway as a convergence point for therapeutic resistance in prostate and potentially other cancer types.

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The Kynurenine Pathway and Cancer: Why Keep It Simple When You Can Make It Complicated

Cited by 34 publications

References 104 publications

Kynurenine Is the Main Metabolite of Tryptophan Degradation by Tryptophan 2,3-Dioxygenase in HepaRG Tumor Cells

Kynurenine Is the Main Metabolite of Tryptophan Degradation by Tryptophan 2,3-Dioxygenase in HepaRG Tumor Cells

Characterization of the Metabolome of Breast Tissues from Non-Hispanic Black and Non-Hispanic White Women Reveals Correlations between Microbial Dysbiosis and Enhanced Lipid Metabolism Pathways in Triple-Negative Breast Tumors

IRF7 impacts on prostate cancer cell survival in response to radiation

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