Immune-regulated IDO1-dependent tryptophan metabolism is source of one-carbon units for pancreatic cancer and stellate cells.
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ABSTRACT:
SUBMITTER: Newman AC
PROVIDER: S-EPMC8189438 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Influenza epidemics remain a leading cause of morbidity and mortality worldwide. In the current study, we investigated the impact of chronological ageing on tryptophan metabolism in response to influenza infection.Examination of metabolites present in plasma collected from critically ill patients identified tryptophan metabolism as an important metabolic pathway utilised specifically in response to influenza. Using a murine model of influenza infection to further these findings illustrated that there was decreased production of kynurenine in aged lung in an indoleamine-pyrrole 2,3-dioxygenase-dependent manner that was associated with increased inflammatory and diminished regulatory responses. Specifically, within the first 7 days of influenza, there was a decrease in kynurenine pathway mediated metabolism of tryptophan, which resulted in a subsequent increase in ketone body catabolism in aged alveolar macrophages. Treatment of aged mice with mitoquinol, a mitochondrial targeted antioxidant, improved mitochondrial function and restored tryptophan metabolism.Taken together, our data provide additional evidence as to why older persons are more susceptible to influenza and suggest a possible therapeutic to improve immunometabolic responses in this population.
| S-EPMC8147522 | biostudies-literature
Project description:Indoleamine 2,3 dioxygenase 1 (IDO1) is an attractive target for cancer immunotherapy. However, IDO1 inhibitors have shown disappointing therapeutic efficacy in clinical trials, mainly because of the activation of the aryl hydrocarbon receptor (AhR). Here, we show a post-transcriptional regulatory mechanism of IDO1 regulated by a proteasome-associated deubiquitinating enzyme, USP14, in colorectal cancer (CRC). Overexpression of USP14 promotes tryptophan metabolism and T-cell dysfunction by stabilizing the IDO1 protein. Knockdown of USP14 or pharmacological targeting of USP14 decreases IDO1 expression, reverses suppression of cytotoxic T cells, and increases responsiveness to anti-PD-1 in a MC38 syngeneic mouse model. Importantly, suppression of USP14 has no effects on AhR activation induced by the IDO1 inhibitor. These findings highlight a relevant role of USP14 in post-translational regulation of IDO1 and in the suppression of antitumor immunity, suggesting that inhibition of USP14 may represent a promising strategy for CRC immunotherapy. IDO1-mediated tryptophan metabolism plays an important role in creating an immunosuppressive tumour microenvironment. Here, the authors show that deubiquitinase USP14 regulates immune suppression by inducing IDO1 stabilization and suggest USP14 as a potential therapeutic target to improve immunotherapy in colorectal cancer.
| S-EPMC9513055 | biostudies-literature
Project description:Abstract OBJECTIVE Glioblastoma (GBM) patients with high intratumoral IDO1 mRNA levels have an associated decrease in survival (Zhai et al., 2017; CCR). IDO1 is an immunosuppressive mediator that metabolizes tryptophan (Trp), and through its associated enzyme activity, has long been recognized to increase immunosuppressive CD4+CD25+FoxP3+ Tregs. Accordingly, we previously showed that the genetic knockdown of IDO1 in murine glioma cells, suppresses intratumoral Treg recruitment and increases animal subject survival. Unexpectedly, however, IDO1 knockdown has no effect on intratumoral Trp metabolism (Zhai et al., 2017; BBI). Further surprisingly, we recently demonstrated that, although IDO1 overexpression increases Treg levels in brain tumors, the pharmacological inhibition of IDO1 metabolism has no effect on Treg accumulation (Ladomersky et al., 2018; CCR). These novel data led us to question the requirement for IDO1 enzyme activity to regulate Tregs in malignant glioma. METHODS Lentiviral vectors encoding: (i) vector control-, (ii) wild-type (WT)-, or (iii) enzyme-null-IDO1, were created by site-directed mutagenesis in a plasmid containing WT, murine, IDO1-GFP cDNA. IDO1-deficient glioma cells from transgenic mice [(ERT2)GFAP→Cre;pTENfl/fl;p53fl/fl;Rbfl/fl;IDO1-/-] were transduced with the modified plasmids. RT-PCR, Western blotting and HPLC confirmed IDO1 expression and enzyme activity, in vitro. Syngeneic IDO1-/- mice were intracranially-engrafted with 2 × 105 modified glioma cells and studied for intratumoral Treg levels. RESULTS The substitution of IDO1 histidine 350, to an alanine (H350A), decreases IDO1 enzyme activity by 90%. Syngeneic mice with intracranial, IDO1 enzyme null (H350A) glioma, have similar intratumoral Treg levels as IDO1 WT glioma, at 25% and 26%, respectively, and is significantly increased as compared to the 5.8% Tregs in vector control glioma (P=0.015). CONCLUSIONS Our data challenge current dogma explaining how IDO1 causes Treg accumulation, and are in-line with the recent IDO1 enzyme inhibitor-focused Phase III clinical trial failure [NCT02752074]. We are now focused on revealing the mechanism underlying IDO1-mediated immunosuppression in malignant glioma.
| S-EPMC6216393 | biostudies-literature
Project description:Abnormal folate one-carbon metabolism (FOCM) is implicated in neural tube defects (NTDs), severe malformations of the nervous system. MTHFR mediates unidirectional transfer of methyl groups from the folate cycle to the methionine cycle and, therefore, represents a key nexus in partitioning one-carbon units between FOCM functional outputs. Methionine cycle inhibitors prevent neural tube closure in mouse embryos. Similarly, the inability to use glycine as a one-carbon donor to the folate cycle causes NTDs in glycine decarboxylase (Gldc)-deficient embryos. However, analysis of Mthfr-null mouse embryos shows that neither S-adenosylmethionine abundance nor neural tube closure depend on one-carbon units derived from embryonic or maternal folate cycles. Mthfr deletion or methionine treatment prevents NTDs in Gldc-null embryos by retention of one-carbon units within the folate cycle. Overall, neural tube closure depends on the activity of both the methionine and folate cycles, but transfer of one-carbon units between the cycles is not necessary.
| S-EPMC5699646 | biostudies-literature
Project description:The tumor microenvironment (TME) in renal cell carcinomas (RCC) is marked by substantial immunosuppression and immune resistance though highly infiltrated by T cells. There is an urgent need to elucidate tumor immune evasion and to develop novel therapeutic target to boost the efficacy of immune checkpoint blockade (ICB) in RCC. Our study uncovers a mechanism wherein the polyadenylate-binding protein PABPC1L modulates indoleamine2, 3dioxygenase1 (IDO1), a prospective candidate for immunotherapy. PABPC1L, markedly upregulated in RCC, correlates with unfavorable prognosis and resistance to ICB. Overexpressed PABPC1L bolsters tryptophan metabolism and induces T-cell dysfunction by stabilizing IDO1. Conversely, silencing PABPC1L diminishes IDO1 expression, mitigates cytotoxic T-cell suppression, and enhances responsiveness to anti-PD-1 therapy. Our findings underscore PABPC1L's crucial role in facilitating immune evasion in RCC, making it a potential addition to ICB therapy.
2024-02-14 | GSE241871 | GEO
Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy: it has a 5-year survival rate of less than 9%. Although surgical resection is an effective treatment for PDAC, only a small number of patients can have their tumors surgically removed. Thus, an urgent need to find new therapeutic targets for PDAC exists. Understanding the molecular mechanism of PDAC development is essential for the treatment of this malignancy. This research aimed to study the mechanisms of pancreatic stellate cells (PSCs), which regulate branched-chain amino acid (BCAA) metabolism in PDAC.MethodsDifferentially expressed proteins were detected via nanoliquid chromatography coupled to mass spectrometry (nano-LC-MS/MS). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment methods were used to find the valine-leucine-isoleucine (BCAA) degradation pathway. The levels of BCAAs in the sera and tissues of patients with PDAC were measured by using nuclear magnetic resonance (NMR). The functions of BCAA concentrations and the effects of activated pancreatic stellate cells (aPSCs) were also evaluated by performing Cell Counting Kit-8, colony formation, and wound healing assays.ResultsA total of 1,519 proteins with significantly differential expression were discovered in PDAC and adjacent tissues by using nano-LC-MS/MS. KEGG pathway enrichment analysis identified the BCAA degradation pathway. The content of BCAA in PDAC clinical samples was up-regulated. However, the addition of different concentrations of BCAA to PDAC cell culture medium failed to promote the proliferation and migration of PDAC cells. Given that analysis based on The Cancer Genome Atlas database showed that the number of aPSCs gradually increased with the progression of PDAC, the effects of aPSCs on PDAC cells were explored. After coculture with aPSCs, PDAC cell proliferation showed a significant increase, and the proteins involved in the BCAA degradation pathway in PDAC cells had also changed.ConclusionsaPSCs could regulate BCAA metabolism to enhance the progression of PDAC, indicating that the regulation of BCAA metabolism may serve as a new therapeutic direction for PDAC.
| S-EPMC8033345 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by an intense fibrotic stromal response and deregulated metabolism. The role of the stroma in PDAC biology is complex and it has been shown to play critical roles that differ depending on the biological context. The stromal reaction also impairs the vasculature, leading to a highly hypoxic, nutrient-poor environment. As such, these tumours must alter how they capture and use nutrients to support their metabolic needs. Here we show that stroma-associated pancreatic stellate cells (PSCs) are critical for PDAC metabolism through the secretion of non-essential amino acids (NEAA). Specifically, we uncover a previously undescribed role for alanine, which outcompetes glucose and glutamine-derived carbon in PDAC to fuel the tricarboxylic acid (TCA) cycle, and thus NEAA and lipid biosynthesis. This shift in fuel source decreases the tumour’s dependence on glucose and serum-derived nutrients, which are limited in the pancreatic tumour microenvironment. Moreover, we demonstrate that alanine secretion by PSCs is dependent on PSC autophagy, a process that is stimulated by cancer cells. Thus, our results demonstrate a novel metabolic interaction between PSCs and cancer cells, in which PSC-derived alanine acts as an alternative carbon source. This finding highlights a previously unappreciated metabolic network within pancreatic tumours in which diverse fuel sources are used to promote growth in an austere tumour microenvironment.
| S-EPMC5228623 | biostudies-literature
Project description:Companion dogs have recently been promoted as an animal model for the study of aging due to their similar disease profile to humans, the sophistication of health assessment and disease diagnosis, and the shared environments with their owners. In addition, dogs show an interesting life history trait pattern where smaller individuals are up to two-fold longer lived than their larger counterparts. While some of the mechanisms underlying this size and longevity trade-off are strongly suspected (i.e., growth hormone/IGF-I), there are likely a number of undiscovered mechanisms as well. Accordingly, we have completed a large-scale global metabolomic profiling of dogs encompassing a range of sizes and ages from three cities across the USA. We found a surprisingly strong location signal in the metabolome, stronger in fact than any signal related to age, breed, or sex. However, after controlling for the effects of location, tryptophan metabolism emerged as significantly associated with weight of the dogs, with small dogs having significantly higher levels of tryptophan pathway metabolites. Overall, our results point toward novel, testable hypotheses about the underlying physiological mechanisms that influence size and longevity in the companion dog and suggest that dogs may be useful in sorting out the complexities of the tryptophan metabolic network.
| S-EPMC7286990 | biostudies-literature
Project description:BackgroundLow chronic vitamin B-6 status can occur in a subset of women who use oral contraceptives (OCs) with uncertain metabolic consequences. An insufficiency of cellular pyridoxal 5'-phosphate (PLP), which is the coenzyme form of vitamin B-6, may impair many metabolic processes including one-carbon and tryptophan metabolism.ObjectiveWe investigated the effects of vitamin B-6 supplementation on the in vivo kinetics of one-carbon metabolism and the concentration of one-carbon and tryptophan metabolites in vitamin B-6-deficient OC users.DesignA primed, constant infusion of [(13)C5]methionine, [3-(13)C]serine, and [(2)H3]leucine was performed on 10 OC users (20-40 y old; plasma PLP concentrations <30 nmol/L) before and after 28 d of supplementation with 10 mg pyridoxine hydrochloric acid/d. In vivo fluxes of total homocysteine remethylation, the remethylation of homocysteine from serine, and rates of homocysteine and cystathionine production were assessed. Targeted metabolite profiling was performed, and data were analyzed by using orthogonal partial least-squares-discriminant analysis and paired t tests adjusted for multiple testing.ResultsPyridoxine supplementation increased the mean ± SD plasma PLP concentration from 25.8 ± 3.6 to 143 ± 58 nmol/L (P < 0.001) and decreased the leucine concentration from 103 ± 17 to 90 ± 20 nmol/L (P = 0.007) and glycine concentration from 317 ± 63 to 267 ± 58 nmol/L (P = 0.03). Supplementation did not affect in vivo rates of homocysteine remethylation or the appearance of homocysteine and cystathionine. A multivariate analysis showed a clear overall effect on metabolite profiles resulting from supplementation. Leucine, glycine, choline, cysteine, glutathione, trimethylamine N-oxide, and the ratios glycine:serine, 3-hydroxykynurenine:kynurenine, 3-hydroxykynurenine:3-hydroxyanthranilic acid, and 3-hydroxykynurenine:anthranilic acid were significant discriminating variables.ConclusionsConsistent with previous vitamin B-6-restriction studies, fluxes of one-carbon metabolic processes exhibited little or no change after supplementation in low-vitamin B-6 subjects. In contrast, changes in the metabolic profiles after supplementation indicated perturbations in metabolism, suggesting functional vitamin B-6 deficiency. This study was registered at clinicaltrials.gov as NCT01128244.
| S-EPMC4548178 | biostudies-literature
Project description:Caloric restriction (CR) improves health span and life span of organisms ranging from yeast to mammals. Understanding the mechanisms involved will uncover future interventions for aging-associated diseases. In budding yeast, Saccharomyces cerevisiae, CR is commonly defined by reduced glucose in the growth medium, which extends both replicative and chronological life span (CLS). We found that conditioned media collected from stationary-phase CR cultures extended CLS when supplemented into nonrestricted (NR) cultures, suggesting a potential cell-nonautonomous mechanism of CR-induced life span regulation. Chromatography and untargeted metabolomics of the conditioned media, as well as transcriptional responses associated with the longevity effect, pointed to specific amino acids enriched in the CR conditioned media (CRCM) as functional molecules, with L-serine being a particularly strong candidate. Indeed, supplementing L-serine into NR cultures extended CLS through a mechanism dependent on the one-carbon metabolism pathway, thus implicating this conserved and central metabolic hub in life span regulation.
| S-EPMC7949035 | biostudies-literature