Targeted Inhibition of Purine Metabolism is Effective in Suppressing Hepatocellular Carcinoma Progression
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA608920 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11186734_1.fastq.gz | Fastqsanger.gz | |||
| SRR11186734_2.fastq.gz | Fastqsanger.gz | |||
| SRR11186735_1.fastq.gz | Fastqsanger.gz | |||
| SRR11186735_2.fastq.gz | Fastqsanger.gz | |||
| SRR11186736_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Tumor-specific metabolic rewiring, intended to confer a survival advantage over non-transformed cells, often offers an opportunity to target cancers. Here, we identify deregulated expression of purine biosynthetic enzymes as a metabolic hallmark in human hepatocellular carcinomas (HCC), with the extent of enzyme upregulation a predictor of clinical outcome. We demonstrate in HCC cell lines, patient-derived xenograft (PDX) organoids and mouse models that inhibition of purine biosynthesis abrogated cancer cell proliferation and tumor growth. Mechanistically, a PI3K-E2F1 axis coordinated purine biosynthetic enzyme expression. Clinically approved inhibitors against PI3K and the purine biosynthetic rate-limiting enzyme IMPDH synergistically reduced the tumor burden in a PDX mouse model. Collectively, our results support targeting purine metabolic reprogramming as a precision therapeutic strategy for HCC patients.
2020-07-06 | GSE145988 | GEO
Project description:Tumor-specific metabolic rewiring, acquired to confer a proliferative and survival advantage over nontransformed cells, represents a renewed focus in cancer therapy development. Hepatocellular carcinoma (HCC), a malignancy that has hitherto been resistant to compounds targeting oncogenic signaling pathways, represents a candidate cancer to investigate the efficacy of selectively antagonizing such adaptive metabolic reprogramming. To this end, we sought to characterize metabolic changes in HCC necessary for tumorigenesis. We analyzed gene expression profiles in three independent large-scale patient cohorts who had HCC. We identified a commonly deregulated purine metabolic signature in tumors with the extent of purine biosynthetic enzyme up-regulation correlated with tumor grade and a predictor of clinical outcome. The functional significance of enhanced purine metabolism as a hallmark in human HCC was then validated using a combination of HCC cell lines, patient-derived xenograft (PDX) organoids, and mouse models. Targeted ablation of purine biosynthesis by knockdown of the rate-limiting enzyme inosine-5'-monophosphate dehydrogenase (IMPDH) or using the drug mycophenolate mofetil (MMF) reduced HCC proliferation in vitro and decreased the tumor burden in vivo. In comparing the sensitivities of PDX tumor organoids to MMF therapy, we found that HCC tumors defined by high levels of IMPDH and guanosine nucleosides were most susceptible to treatment. Mechanistically, a phosphoinositide 3-kinase (PI3K)-E2F transcription factor 1 (E2F1) axis coordinated purine biosynthetic enzyme expression, deregulation of which altered the activity of mitogen-activated protein kinase/RAS signaling. Simultaneously abolishing PI3K signaling and IMPDH activity with clinically approved inhibitors resulted in greatest efficacy in reducing tumor growth in a PDX mouse model. Conclusion: Enhanced purine metabolic activity regulated by PI3K pathway-dependent activation of E2F1 promotes HCC carcinogenesis, suggesting the potential for targeting purine metabolic reprogramming as a precision therapeutic strategy for patients with HCC.
| S-EPMC7471427 | biostudies-literature
Project description:To investigate whether BRD4-chromatin binding is modulated by purine levels, we performed BRD4 ChIP-seq in cells with SLC nucleoside transporters knockout, or cells with de novo purine synthesis inhibitor 6-MP treatment. (+)-JQ1, an inhibitor which disrupts BRD4 and acetylated histone binding, was used as a positive control.
2021-04-17 | GSE167374 | GEO
Project description:Curto1998 - purine metabolism
This is a purine metabolism model that is geared toward studies of gout.
The model uses Generalized Mass Action (GMA; i.e. power law) descriptions of reaction rate laws.
Such descriptions are local approximations that assume independent substrate binding.
This model is described in the article:
Mathematical models of
purine metabolism in man.
Curto R, Voit EO, Sorribas A,
Cascante M.
Math Biosci 1998 Jul; 151(1):
1-49
Abstract:
Experimental and clinical data on purine metabolism are
collated and analyzed with three mathematical models. The first
model is the result of an attempt to construct a traditional
kinetic model based on Michaelis-Menten rate laws. This attempt
is only partially successful, since kinetic information, while
extensive, is not complete, and since qualitative information
is difficult to incorporate into this type of model. The data
gaps necessitate the complementation of the Michaelis-Menten
model with other functional forms that can incorporate
different types of data. The most convenient and established
representations for this purpose are rate laws formulated as
power-law functions, and these are used to construct a
Complemented Michaelis-Menten (CMM) model. The other two models
are pure power-law-representations, one in the form of a
Generalized Mass Action (GMA) system, and the other one in the
form of an S-system. The first part of the paper contains a
compendium of experimental data necessary for any model of
purine metabolism. This is followed by the formulation of the
three models and a comparative analysis. For physiological and
moderately pathological perturbations in metabolites or
enzymes, the results of the three models are very similar and
consistent with clinical findings. This is an encouraging
result since the three models have different structures and
data requirements and are based on different mathematical
assumptions. Significant enzyme deficiencies are not so well
modeled by the S-system model. The CMM model captures the
dynamics better, but judging by comparisons with clinical
observations, the best model in this case is the GMA model. The
model results are discussed in some detail, along with
advantages and disadvantages of each modeling strategy.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000015.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000015 | BioModels
Project description:To investigate the transcriptional profile in two BRD4 reporter clones (REDS1 and REDS15) with purine metabolism perturbation
2021-04-17 | GSE168099 | GEO
Project description:Purine catabolism is regarded as a housekeeping function that remobilizes nitrogen for plant growth and development. However, emerging evidence suggests that certain purine metabolites might contribute to stress protection of plants. Here, we show that in Arabidopsis, the intermediary metabolite allantoin plays a role in abiotic stress tolerance via activation of abscisic acid (ABA) metabolism. The aln loss-of-function of ALN, encoding allantoinase, results in increased allantoin accumulation, genome-wide up-regulation of stress-related genes, and enhanced tolerance to drought-shock and osmotic stress in aln mutant seedlings. This phenotype is not caused by a general response to purine catabolism inhibition, but rather results from a specific effect of allantoin. Allantoin activates ABA production both through increased transcription of NCED3, encoding a key enzyme in ABA biosynthesis, and through post-translational activation via high-molecular-weight complex formation of BG1, a ß-glucosidase hydrolyzing glucose-conjugated ABA. Exogenous application of allantoin to wild-type plants also activates the two ABA-producing pathways that lead to ABA accumulation and stress-responsive gene expression, but this effect is abrogated in ABA-deficient and BG1-knockout mutants. We propose that purine catabolism functions not only in nitrogen metabolism, but also in stress tolerance by influencing ABA production, which is mediated by the possible regulatory action of allantoin. Compared analysis of the transcriptomes of 2-week-old Arabidopsis seedlings from an allantoin-accumulating mutant genotype versus wild type background Col-0 (2 independent biological replicates per genotype). The allantoin-accumulating mutant in Col-0 background was the aln-1 mutant allele in allantoinase (ALN) (abbreviated as aln).
2014-01-16 | E-GEOD-44922 | biostudies-arrayexpress
Project description:The ability of Leishmania to survive in their insect or mammalian host is dependent upon an ability to sense and adapt to changes in the microenvironment. However, little is known about the molecular mechanisms underlying the parasite response to environmental changes, such as nutrient availability. To elucidate nutrient stress response pathways in Leishmania donovani, we have used purine starvation as the paradigm. The salvage of purines from the host milieu is obligatory for parasite replication; nevertheless, purine-starved parasites can persist in culture without supplementary purine for over 3 months, indicating that the response to purine starvation is robust and engenders parasite survival under conditions of extreme scarcity. To understand metabolic reprogramming during purine starvation we have employed global approaches. Whole proteome comparisons between purine-starved and purine-replete parasites over a 6-48 h span have revealed a temporal and coordinated response to purine starvation. Purine transporters and enzymes involved in acquisition at the cell surface are upregulated within a few hours of purine removal from the media, while other key purine salvage components are upregulated later in the time-course and more modestly. After 48 h, the proteome of purine-starved parasites is extensively remodeled and adaptations to purine stress appear tailored to deal with both purine deprivation and general stress. To probe the molecular mechanisms affecting proteome remodeling in response to purine starvation, comparative RNA-seq analyses, qRT-PCR, and luciferase reporter assays were performed on purine-starved versus purine-replete parasites. While the regulation of a minority of proteins tracked with changes at the mRNA level, for many regulated proteins it appears that proteome remodeling during purine stress occurs primarily via translational and post-translational mechanisms. One mRNA sample from each of Purine-Starved and Purine-Replete cells were analyzed using SL RNA-Seq methodology
2014-02-01 | E-GEOD-48394 | biostudies-arrayexpress
Project description:In the McSC lineage in zebrafish, Aldh2 activity is an important source of formate through its metabolism of its substrate formaldehyde. This formate is required as input into the folate cycle, in particular de novo purine biosynthesis. This scRNA-seq experiment was conducted to investigate the global effects of Aldh2 inhibition on the transcriptomes of isolated McSCs.
2022-05-09 | GSE183868 | GEO
Project description:Elevated Extracellular Purine Nucleotides Impair Muscle Regeneration in Diabetic Mice by Suppressing Early Activation of Muscle Satellite Cells
| PRJNA733661 | ENA
Project description:Purine catabolism is regarded as a housekeeping function that remobilizes nitrogen for plant growth and development. However, emerging evidence suggests that certain purine metabolites might contribute to stress protection of plants. Here, we show that in Arabidopsis, the intermediary metabolite allantoin plays a role in abiotic stress tolerance via activation of abscisic acid (ABA) metabolism. The aln loss-of-function of ALN, encoding allantoinase, results in increased allantoin accumulation, genome-wide up-regulation of stress-related genes, and enhanced tolerance to drought-shock and osmotic stress in aln mutant seedlings. This phenotype is not caused by a general response to purine catabolism inhibition, but rather results from a specific effect of allantoin. Allantoin activates ABA production both through increased transcription of NCED3, encoding a key enzyme in ABA biosynthesis, and through post-translational activation via high-molecular-weight complex formation of BG1, a ß-glucosidase hydrolyzing glucose-conjugated ABA. Exogenous application of allantoin to wild-type plants also activates the two ABA-producing pathways that lead to ABA accumulation and stress-responsive gene expression, but this effect is abrogated in ABA-deficient and BG1-knockout mutants. We propose that purine catabolism functions not only in nitrogen metabolism, but also in stress tolerance by influencing ABA production, which is mediated by the possible regulatory action of allantoin.
2014-01-16 | GSE44922 | GEO