Molecular Cell, Journal Year: 2021, Volume and Issue: 81(18), P. 3731 - 3748
Published: Sept. 1, 2021
Language: Английский
Cancer Letters, Journal Year: 2022, Volume and Issue: 548, P. 215751 - 215751
Published: June 16, 2022
Language: Английский
Citations
127
Molecular Cell, Journal Year: 2022, Volume and Issue: 82(5), P. 920 - 932.e7
Published: March 1, 2022
Language: Английский
Citations
100
Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)
Published: July 24, 2023
Immunosuppression is a hallmark of pancreatic ductal adenocarcinoma (PDAC), contributing to early metastasis and poor patient survival. Compared the localized tumors, current standard-of-care therapies have failed improve survival patients with metastatic PDAC, that necessecitates exploration novel therapeutic approaches. While immunotherapies such as immune checkpoint blockade (ICB) vaccines emerged promising treatment modalities in certain cancers, limited responses been achieved PDAC. Therefore, specific mechanisms regulating response immunotherapy must be explored. The immunosuppressive microenvironment driven by oncogenic mutations, tumor secretome, non-coding RNAs, microbiome persists throughout PDAC progression, allowing neoplastic cells grow locally metastasize distantly. escaping host surveillance are unique molecular, immunological, metabolic characteristics. Following chemokine exosomal guidance, these organ-specific pre-metastatic niches (PMNs) constituted local resident cells, stromal fibroblasts, suppressive metastasis-associated macrophages, neutrophils, myeloid-derived suppressor cells. differs from primary tumors cell composition, functionality, metabolism. Thus far, multiple molecular pathways, distinct identified dampen effector functions, confounding This review describes major immunoregulatory pathways contribute progression limit outcomes Overall, we highlight vulnerabilities attributable factors discuss whether targeting immunological "hot spots" could immunotherapies.
Language: Английский
Citations
41
Journal of Biological Chemistry, Journal Year: 2023, Volume and Issue: 299(6), P. 104827 - 104827
Published: May 23, 2023
Regulated tryptophan metabolism by immune cells has been associated with the promotion of tolerance and poor outcomes in cancer. The main focus research centered on local depletion IDO1, an intracellular heme-dependent oxidase that converts to formyl-kynurenine. This is first step a complex pathway supplying metabolites for de novo NAD+ biosynthesis, 1-carbon metabolism, myriad kynurenine derivatives which several act as agonists arylhydrocarbon receptor (AhR). Thus, express IDO1 deplete while generating downstream metabolites. We now know another enzyme, secreted L-amino acid IL4i1 also generates bioactive from tryptophan. In tumor microenvironments, have overlapping expression patterns, especially myeloid cells, suggesting two enzymes control network tryptophan-specific metabolic events. New findings about shown both generate suite suppress oxidative cell death ferroptosis. within inflammatory environments, simultaneously essential amino depletion, AhR activation, suppression ferroptosis, biosynthesis key intermediates. Here, we summarize recent advances this field, focusing speculate inhibition remains viable adjuvant therapy solid tumors, effects must be accounted for, potentially may need inhibited at same time produce positive cancer therapy. 20 proteinogenic acids sustain cellular biochemistry by: (i) translation, (ii) source carbon skeletons nitrogen energy generation nucleotide (iii) "shuttles" move molecules different compartments tasks such malate-aspartate shuttle or methionine major methyl donor 1-carbon-folate cycle. Several dedicated additional functions precursors signaling (neurotransmitters), cofactors (heme, glycine), redox protective glutathione (from glycine, cysteine, glutamate). Because these diverse functions, balance their sources synthesis, transport, scavenging protein sinks therefore constantly monitor deficiencies excesses all acids. An facet concerns biochemical where regulated enzyme consumes distinct products. setting, events occur simultaneously: can become limiting, triggering defenses including increased reduction activation autophagy (and related measures) products modulatory effects. define "regulated" here specific, induced activity metabolizing via cytokines, pathogen products, other pathways, acquisition not normally present type interest. case latter, many patterns differ origin, presumably way obtain resources growth evade control. acid-metabolizing cytokines are arginases (ARG1 cytoplasm ARG2 mitochondria), oxidases (indole, 2,3 dioxygenase), TDO2 (tryptophan dioxygenase) (Interleukin 4-induced 1, oxidase) (1Murray P.J. Amino auxotrophy system immunological nodes.Nat. Immunol. 2016; 17: 132-139Google Scholar). Three constitutive functions: ARG1 metabolize dietary arginine hepatocytes, most some mitochondria. However, system, highly expressed thereby consume microenvironments unexpected Scholar, 2Grohmann U. Bronte V. Control response metabolism.Immunol. Rev. 2010; 236: 243-264Google Accordingly, intersect elements regulation biology. types, uncoupled regulatory signals cells: discuss aspect briefly counterpoint metabolism. note intersection microbial indoles microbiota, host physiology emerging important topic (3Hezaveh K. Shinde R.S. Klotgen A. Halaby M.J. Lamorte S. Ciudad M.T. et al.Tryptophan-derived activate aryl hydrocarbon tumor-associated macrophages anti-tumor immunity.Immunity. 2022; 55: 324-340.e8Google 4Roager H.M. Licht T.R. Microbial catabolites health disease.Nat. Commun. 2018; 9: 3294Google element too large scope included herein. IL4i1. Summaries biology clinical significance arginase published 5Platten M. Nollen E.A.A. Rohrig U.F. Fallarino F. Opitz C.A. Tryptophan common therapeutic target cancer, neurodegeneration beyond.Nat. Drug Discov. 2019; 18: 379-401Google 6Peranzoni E. Marigo I. Dolcetti L. Ugel Sonda N. Taschin al.Role immunity immunopathology.Immunobiology. 2007; 212: 795-812Google 7Eming S.A. Murray Pearce E.J. Metabolic orchestration wound healing response.Cell Metab. 2021; 33: 1726-1743Google Scholar) will covered. Nevertheless, general sense, arginine- tryptophan-metabolizing cause similar outputs: consumed product generated. regard, practical conceptual issues underline experimental First, realm, quantification intrinsically temporal versus experimentally often environments. do yet full understanding cell-specific limitation, vary cell. Indeed, substantial differences adaptation malignant (8Shorthouse D. Bradley J. Critchlow S.E. Bendtsen C. Hall B.A. Heterogeneity line landscape.Mol. Syst. Biol. 18e11006Google Scholar), normal muscle neuron T naturally requirements linked specific functions. Further, only rudimentary how detect (9Wolfson R.L. Sabatini D.M. dawn age sensors mTORC1 pathway.Cell 2017; 26: 301-309Google adjust correct amounts needed. Second, curiosity arginases, IDO1/TDO2 IL4i1, tryptophan-centric nature compared threonine branched-chain specificity suggests degradation pathways evolved immune-specific relative As here, knowledge newly discovered rapidly advancing. it limitation For example, valine specifically collapses one electron transport chain (10Thandapani P. Kloetgen Witkowski Glytsou Lee A.K. Wang al.Valine tRNA levels availability regulate I assembly leukaemia.Nature. 601: 428-433Google eliminates stem bone marrow (11Taya Y. Ota Wilkinson A.C. Kanazawa Watarai H. Kasai al.Depleting permits nonmyeloablative mouse hematopoietic transplantation.Science. 354: 1152-1155Google cases, controlled manipulation food media rather than controls degradation. By contrast, depends natural endogenous limitation. upregulated locally depleting aromatic acids) immunomodulatory microenvironment (Fig. 1A). While (12Boulland M.L. Marquet Molinier-Frenkel Moller Guiter Lasoudris al.Human IL4I1 L-phenylalanine mature dendritic inhibits T-lymphocyte proliferation.Blood. 110: 220-227Google each occurs spatially separated manner. operate catabolize intra- extracellular milieu. catalyzes oxidation indole ring N-formyl-kynurenine rate-limiting reaction (Kyn) pathway. Kyn supplies substrates synthesis (13Covarrubias A.J. Perrone R. Grozio Verdin NAD(+) its roles processes during ageing.Nat. Mol. Cell 22: 119-141Google 14Cervenka Agudelo L.Z. Ruas J.L. Kynurenines: tryptophan's exercise, inflammation, mental health.Science. 357eaaf9794Google 15Badawy A.A. Kynurenine metabolism: functional aspects.Int. Res. 101178646917691938Google 1B). N-formyl-Kyn subsequently deformylated constitutively arylformamidase (AFMID) formyl group (16Newman Falcone Huerta Uribe Zhang T. Athineos Pietzke al.Immune-regulated Ido1-dependent one-carbon units pancreatic stellate cells.Mol. Cell. 81: 2290-2302.e7Google branch pathway, converted into 3-hydroxykynurenine (3HK) monooxygenase (KMO) further 3-hydroxyanthranilic (3HAA) kynureninase (KYNU). Subsequently, 3-hydroxyanthranilate-3,4-dioxygenase (HAAO) 2-amino-3-carboxymuconic semialdehyde (2ACS) 3HAA, spontaneously cyclize quinolinic (QA), picolinic glutaryl-CoA. Glutaryl-CoA feeds Krebs cycle, whereas QA substrate kynurenic (KynA) aminotransferase (KAT) isoenzymes (15Badawy KynA ligands (AhR), ligand-activated transcription factor involved multitude physiological (17Gutierrez-Vazquez Quintana F.J. Regulation receptor.Immunity. 48: 19-33Google discussed detail later. A notable KYNU KAT isozymes require pyridoxyl 5′-phosphate (active vitamin B6) cofactor could play role regulating output branches Overall, catalyzing modulate availability, emergence metabolites, fuels tryptophan-derived units. conjunction ultimately determine flux final Therefore, single relevant thus appears underexplored Besides catalyze IDO2, homolog IDO1. genes encoding IDO2 located tandem arrangement, they ancestral gene (18Yuasa H.J. Ball Ho Y.F. Austin C.J. Whittington C.M. Belov al.Characterization evolution vertebrate indoleamine 2, 3-dioxygenases IDOs monotremes marsupials.Comp. Biochem. Physiol. B 2009; 153: 137-144Google 19Metz Duhadaway J.B. Kamasani Laury-Kleintop Muller Prendergast G.C. Novel catabolic Ido2 preferred antitumor 2,3-dioxygenase inhibitory compound D-1-methyl-tryptophan.Cancer 67: 7082-7087Google exhibits much lower catalytic (Km 500–1000 fold lower) limited information context immunoregulation (20Mondanelli G. Mandarano Belladonna Suvieri Pelliccia Bellezza al.Current challenges immunotherapy.Front. 12679953Google 21Merlo L.M.F. Peng W. DuHadaway Montgomery J.D. al.The mediates autoimmune arthritis through nonenzymatic mechanism.J. 208: 571-581Google isoenzyme review. mainly liver responsible ∼90% nutritional types (notably gliomas) resistance (22Ye Z. Yue Shi Shao Wu Role Ido TDO cancers diseases implications.J. Cancer. 10: 2771-2782Google (LAAO) responses was described 1997 (23Chu C.C. Paul W.E. Fig1, interleukin isolated cDNA representational difference analysis.Proc. Natl. Acad. Sci. 1997; 94: 2507-2512Google IL-4-inducible murine cells. producers (DCs) (24Marquet Cousin Puiffe Martin-Garcia Baud al.Dichotomy between factors inducing immunosuppressive IL-4-induced 1 (IL4I1) lymphocytes mononuclear phagocytes.Eur. 40: 2557-2568Google extensively below. respects, unfortunate name confused IL-4 receptor. Moreover, peripherally since expression, protein's function indicated. relatives snake venoms, provided us clue mammalian (25Zeitler Fiore Meyer Russier Zanella Suppmann al.Anti-ferroptotic mechanism IL4i1-mediated metabolism.Elife. 10e64806Google describe called LAAOs. official mammals. contrast additionally metabolizes phenylalanine tyrosine 25Zeitler 26Sadik Somarribas Patterson L.F. Ozturk Mohapatra S.R. Panitz Secker P.F. al.IL4I1 checkpoint activates AHR promotes progression.Cell. 2020; 182: 1252-1270.e34Google 27Mason J.M. Naidu M.D. Barcia Porti Chavan S.S. Chu gene-1 leukocyte unusual acidic pH preference lysosomal localization.J. 2004; 173: 4561-4567Google fact, shows highest affinity towards studies others suggest central mediated IL4i1-dependent 28Zhang X. Gan Li Su Tan al.Endogenous pyruvate IL4I1.J. Agric. 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Rep. 781Google When enzymatic recombinant Indian cobra (Naja naja) LAAO, found sufficient toxic production ammonia, catabolism phenylalanine, tyrosine, produces phenylpyruvate (PP), 4-hydroxyphenylpyruvate (4HPP), indole-3-pyruvate (I3P), respectively Out I3P greatest anti-oxidative properties secreted, space requires subsequent import well-resolved little known I3P, recently reported give rise KynA, indole-3-acetic (I3AA), indole-3-aldehyde (I3A) indole-3-lactate (I3L) (26Sadik (non-transformed) baseline negligible. Instead, inducible. After stimulation 2 interferons (IFNs), IFN-γ, transcript thousands above STAT1 (35Fiore regulation.Curr. Opin. 70: 7-14Google 36Fiore Zeitler Gross Hiller M.K. Parker al.Kynurenine importation SLC7A11 propagates anti-ferroptotic signaling.Mol. 82: 920-932.e927Google 37Chon S.Y. Hassanain H.H. Pine Gupta S.L. Involvement interferon-gamma-regulated gene.J. Interferon Cytokine 1995; 15: 517-526Google 38Du M.X. Sotero-Esteva W.D. Taylor M.W. Analysis IFN-gamma.J. 2000; 20: 133-142Google any responds IFN-γ cell-type difficult tease apart. Depending analyzed, underestimated (39Desvignes Ernst Interferon-gamma-responsive nonhematopoietic Mycobacterium tuberculosis.Immunity. 31: 974-985Google centers biology, (especially ovarian endometrial tumors) property readily observed single-cell RNA sequencing (scRNAseq) datasets foundational concept behind use inhibitors (40Van den Eynde B.J. Van Baren Baurain J.F. Is there future Ido1 after failure epacadostat melanoma?.Annu. Cancer 4: 241-256.10Google restore immunity, blocked tryptophan-deficient milieu resulting IDO1+ expressing question tumor-specific transcriptional involvement IFN-independent driving open up new opportunities manipulating (TME) (41Hennequart Pilotte Cane Hoffmann Stroobant Plaen al.Constitutive tumors driven cyclooxygenase-2 intrinsic cancer.Immunol. 5: 695-709Google 42Theate van Moulin Larrieu Renauld J.C. al.Extensive profiling tumoral tissues 2015; 3: 161-172Google 43Uyttenhove Theate Colau Parmentier al.Evidence based 2,3-dioxygenase.Nat. Med. 2003; 1269-1274Google point, very understood extrinsic It possible cell-intrinsic "hijack" enhanced survival. So far, questions remain largely unexplored vital answer if properly understand monocyte-derived DCs residing granulomas (TAMs) (44Carbonnelle-Puscian Copie-Bergm
Language: Английский
Citations
39
FEBS Journal, Journal Year: 2023, Volume and Issue: 291(3), P. 412 - 429
Published: May 2, 2023
Amino acids act as versatile nutrients driving cell growth and survival, especially in cancer cells. acid metabolism comprises numerous metabolic networks is closely linked with intracellular redox balance epigenetic regulation. Reprogrammed amino has been recognized a ubiquitous feature tumour This review outlines the of several primary cells highlights pivotal role sustaining homeostasis regulating modification response to oxidative genetic stress
Language: Английский
Citations
37
Biomarker Research, Journal Year: 2023, Volume and Issue: 11(1)
Published: May 5, 2023
The serine-glycine-one-carbon (SGOC) metabolic pathway is critical for DNA methylation, histone and redox homeostasis, in addition to protein, lipid, nucleotide biosynthesis. SGOC a crucial network tumorigenesis, wherein the outputs are required cell survival proliferation particularly likely be co-opted by aggressive cancers. metabolism provides an integration point of clinical significance. mechanism how this regulated key understanding tumor heterogeneity overcoming potential recurrence. Herein, we review role cancer focusing on enzymes with tumor-promoting functions important products physiological significance tumorigenesis. In addition, introduce ways which cells acquire use one-carbon unit, discuss recently clarified tumorigenesis development, as well their relationship immunotherapy ferroptosis. targeting may therapeutic strategy improve outcomes
Language: Английский
Citations
35
EBioMedicine, Journal Year: 2024, Volume and Issue: 102, P. 105056 - 105056
Published: March 11, 2024
Language: Английский
Citations
17
Science, Journal Year: 2024, Volume and Issue: 385(6704)
Published: May 23, 2024
After infection of B cells, Epstein-Barr virus (EBV) engages host pathways that mediate cell proliferation and transformation, contributing to the propensity drive immune dysregulation lymphomagenesis. We found EBV protein EBNA2 initiates nicotinamide adenine dinucleotide (NAD) de novo biosynthesis by driving expression metabolic enzyme indoleamine 2,3-dioxygenase 1 (IDO1) in infected cells. Virus-enforced NAD production sustained mitochondrial complex I activity, match adenosine triphosphate (ATP) with bioenergetic requirements transformation. In transplant patients, IDO1 EBV-infected a serum signature increased preceded development lymphoma. humanized mice EBV, inhibition reduced both viremia Virus-orchestrated is therefore druggable vulnerability EBV-driven opening therapeutic possibilities for EBV-related diseases.
Language: Английский
Citations
17
Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)
Published: Oct. 30, 2024
Language: Английский
Citations
15
Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(8)
Published: Aug. 1, 2024
Abstract Pancreatic cancer is an aggressive with a poor prognosis. Metabolic abnormalities are one of the hallmarks pancreatic cancer, and cells can adapt to biosynthesis, energy intake, redox needs through metabolic reprogramming tolerate nutrient deficiency hypoxic microenvironments. use glucose, amino acids, lipids as maintain malignant growth. Moreover, they also metabolically interact in tumour microenvironment change cell fate, promote progression, even affect immune responses. Importantly, changes at body level deserve more attention. Basic research clinical trials based on targeted therapy or combination other treatments full swing. A comprehensive in-depth understanding regulation will not only enrich mechanisms disease progression but provide inspiration for new diagnostic therapeutic approaches.
Language: Английский
Citations
14