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![Purine and pyrimidine biosynthesis pathways. The inset provides a legend of nucleotide metabolism genes with direct MYC binding found by ChIP-PET in P493-6 model [33]. doi:10.1371/journal.pone.0002722.g001](profile/Chi-Dang/publication/51403832/figure/fig9/AS:669701810188290@1536680762098/Purine-and-pyrimidine-biosynthesis-pathways-The-inset-provides-a-legend-of-nucleotide.png)
Purine and pyrimidine biosynthesis pathways. The inset provides a legend of nucleotide metabolism genes with direct MYC binding found by ChIP-PET in P493-6 model [33]. doi:10.1371/journal.pone.0002722.g001
Source publication
The c-Myc transcription factor is a master regulator and integrates cell proliferation, cell growth and metabolism through activating thousands of target genes. Our identification of direct c-Myc target genes by chromatin immunoprecipitation (ChIP) coupled with pair-end ditag sequencing analysis (ChIP-PET) revealed that nucleotide metabolic genes a...
Contexts in source publication
Context 1
... cells express high levels of Myc in the absence of tetracycline with a Burkitt's lymphoma-like cytologic morphology. Within the purine and pyrimidine de novo synthesis pathway, 11 genes were bound directly by Myc in the ChIP-PET study ( Figure 1). Genes encoding almost every step involved in the purine and pyrimidine de novo synthesis pathway are up-regulated after MYC induction in the P493-6 system as determined by 5 microarray experiments on biological duplicates or triplicates. ...
Context 2
... sought to study the expression of PPAT, PAICS, IMPDH1, IMPDH2 and DHODH in these livers. We were interested in PPAT and PAICS because they share a bi-directional promoter and are both key enzymes in purine synthesis (Figure 1). For IMPDH and DHODH, there are clinically available small molecules that could specifically inhibit their function separately. ...
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The c-myc proto-oncogene is activated by translocation in Burkitt's lymphoma and substitutions in codon 58 stabilize the Myc protein or augment its oncogenic potential. In wild-type Myc, phosphorylation of Ser 62 and Thr 58 provides a landing pad for the peptidyl prolyl-isomerase Pin1, which in turn promotes Ser 62 dephosphorylation and Myc degrada...
Burkitt's lymphoma (BL) originates from a germinative centre cell that loses proliferation control due to activation of the c-myc gene. Apoptosis resistance is a major cause of chemotherapy failure in most kinds of cancers, including BL. The high rate of apoptosis seen in the early steps of genesis of BL is followed by a subsequent development of i...
Abnormalities of the MYC oncogene on chromosome 8 are characteristic of Burkitt lymphoma and other aggressive B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL). We recently described a colorimetric in situ hybridization (CISH) method for detecting extra copies of the MYC gene in DLBCL and the frequent occurrence of excess copies of...
Citations
... Kou et al. showed that Gln was significantly more consumed by breast cancer cells, whereas Glu and Pro were most released into the media by breast cancer cells [33]. It is known that Gln performs several functions in tumor cells: Gln is an intermediate metabolite for the synthesis of nucleotides and non-essential amino acids and allows for the uptake of other essential amino acids, while Gln is removed from the cell in exchange for the uptake of another amino acid; Gln plays a role in the regeneration of intermediate metabolites of the tricarboxylic acid cycle [34], and it is also important for the synthesis of glutathione [35]. Glutaminase, an enzyme that converts Gln to Glu, is overexpressed in breast cancer, especially in TNBC tumors compared to HER2 and luminal subtypes [36]. ...
The study of salivary amino acid profiles has attracted the attention of researchers, since amino acids are actively involved in most metabolic processes, including breast cancer. In this study, we analyzed the amino acid profile of saliva in a sample including all molecular biological subtypes of breast cancer to obtain a more complete picture and evaluate the potential utility of individual amino acids or their combinations for diagnostic purposes. This study included 116 patients with breast cancer, 24 patients with benign breast disease, and 25 healthy controls. From all patients, strictly before the start of treatment, saliva samples were collected, and the quantitative content of 26 amino acids was determined. Statistically significant differences between the three groups are shown in the content of Asp, Gly, Leu + Ile, Orn, Phe, Pro, Thr, and Tyr. To differentiate the three groups from each other, a decision tree was built. To construct it, we selected those amino acids for which the change in concentrations in the subgroups was multidirectional (GABA, Hyl, Arg, His, Pro, and Car). For the first time, it is shown that the amino acid profile of saliva depends on the molecular biological subtype of breast cancer. The most significant differences are shown for the luminal B HER2-positive and TNBC subgroups. In our opinion, it is critically important to consider the molecular biological subtype of breast cancer when searching for potential diagnostic markers.
... Small cell carcinoma, which has a high mitotic count, has a very poor prognosis (2-year survival rate of approximately 8%) (Nicholson et al. 2016). Both glucose and nitrogen metabolism are altered during the malignant progression of carcinoma (Kodama et al. 2020;Zhang et al. 2017), and elevated levels of c-Myc induce the expression of enzymes, such as phosphoribosyl pyrophosphate aminotransferase (PPAT), which is involved in nucleotide biosynthetic pathways (Cunningham et al. 2014;Liu et al. 2008). The fate of glutamine nitrogen is steered from the anaplerotic pathway to the tricarboxylic acid cycle in the mitochondria to enhance nucleotide biosynthesis (Kodama et al. 2020). ...
Purpose
Visualizing mitochondria in cancer cells from human pathological specimens may improve our understanding of cancer biology. However, using immunohistochemistry to evaluate mitochondria remains difficult because almost all cells contain mitochondria and the number of mitochondria per cell may have important effects on mitochondrial function. Herein, we established an objective system (Mito-score) for evaluating mitochondria using machine-based processing of hue, saturation, and value color spaces.
Methods
The Mito-score was defined as the number of COX4 (mitochondrial inner membrane) immunohistochemistry-positive pixels divided by the number of nuclei per cell. The system was validated using four lung cancer cell lines, normal tissues, and lung cancer tissues (199 cases).
Results
The Mito-score correlated with MitoTracker, a fluorescent dye used to selectively label and visualize mitochondria within cells under a microscope (R² = 0.68) and with the number of mitochondria counted using electron microscopy (R² = 0.79). Histologically, the Mito-score of small cell carcinoma (57.25) was significantly lower than that of adenocarcinoma (147.5, p < 0.0001), squamous cell carcinoma (120.6, p = 0.0004), and large cell neuroendocrine carcinoma (111.8, p = 0.002).
Conclusion
The Mito-score method enables the analysis of the mitochondrial status of human formalin-fixed paraffin-embedded specimens and may provide insights into the metabolic status of cancer.
... Taken together, our study revealed that the Wnt/β-catenin signalling pathway may be a master regulator of purine metabolic reprogramming in oxaliplatin resistance. However, c-Myc also serves as an oncogene that directly induces enhanced expression of target enzymes involved in the metabolism of a variety of enzymes, including IMPDH2 [43]. Thus, the mechanism underlying the interaction between c-Myc and the Wnt/β-catenin pathway and IMPDH2 in CRC oxaliplatin resistance remains to be assessed in our future research. ...
Background
Oxaliplatin resistance usually leads to therapeutic failure and poor prognosis in colorectal cancer (CRC), while the underlying mechanisms are not yet fully understood. Metabolic reprogramming is strongly linked to drug resistance, however, the role and mechanism of metabolic reprogramming in oxaliplatin resistance remain unclear. Here, we aim to explore the functions and mechanisms of purine metabolism on the oxaliplatin-induced apoptosis of CRC.
Methods
An oxaliplatin-resistant CRC cell line was generated, and untargeted metabolomics analysis was conducted. The inosine 5ʹ-monophosphate dehydrogenase type II (IMPDH2) expression in CRC cell lines was determined by quantitative real-time polymerase chain reaction (qPCR) and western blotting analysis. The effects of IMPDH2 overexpression, knockdown and pharmacological inhibition on oxaliplatin resistance in CRC were assessed by flow cytometry analysis of cell apoptosis in vivo and in vitro.
Results
Metabolic analysis revealed that the levels of purine metabolites, especially guanosine monophosphate (GMP), were markedly elevated in oxaliplatin-resistant CRC cells. The accumulation of purine metabolites mainly arose from the upregulation of IMPDH2 expression. Gene set enrichment analysis (GSEA) indicated high IMPDH2 expression in CRC correlates with PURINE_METABOLISM and MULTIPLE-DRUG-RESISTANCE pathways. CRC cells with higher IMPDH2 expression were more resistant to oxaliplatin-induced apoptosis. Overexpression of IMPDH2 in CRC cells resulted in reduced cell death upon treatment with oxaliplatin, whereas knockdown of IMPDH2 led to increased sensitivity to oxaliplatin through influencing the activation of the Caspase 7/8/9 and PARP1 proteins on cell apoptosis. Targeted inhibition of IMPDH2 by mycophenolic acid (MPA) or mycophenolate mofetil (MMF) enhanced cell apoptosis in vitro and decreased in vivo tumour burden when combined with oxaliplatin treatment. Mechanistically, the Wnt/β-catenin signalling was hyperactivated in oxaliplatin-resistant CRC cells, and a reciprocal positive regulatory mechanism existed between Wnt/β-catenin and IMPDH2. Blocking the Wnt/β-catenin pathway could resensitize resistant cells to oxaliplatin, which could be restored by the addition of GMP.
Conclusions
IMPDH2 is a predictive biomarker and therapeutic target for oxaliplatin resistance in CRC.
... PPP-related enzymes, including transketolase (TKT) and G6PD, are overexpressed in several malignancies like breast, lung, ovarian, and colorectal cancer, wherein they are known to promote the development of chemoresistance [51]. Another way in which Akt signaling controls nucleotide synthesis is the regulation of Myc activity, as Myc increases the expression of metabolite precursors and many enzymes involved in purine and pyrimidine synthesis [52]. The activation of mTOR downstream branch of PI3K/Akt signaling regulates nucleotide synthesis de novo on both the transcriptional and posttranslational levels. ...
Simple Summary
The PI3K/Akt/mTOR pathway plays a crucial role in cancer, including leukemia. Abnormalities in this pathway drive carcinogenesis by inducing uncontrolled growth, increased survival, and treatment resistance. The abovementioned pathway is also disrupted in various types of leukemia, which makes it a potential therapeutic target for this disease. Current treatment approaches for leukemia are limited and fraught with numerous side effects. This review article aims to summarize recent research data on inhibitors of the PI3K/Akt/mTOR pathway. Inhibition of this pathway may potentially provide improved treatment outcomes for leukemia.
Abstract
Blood malignancies remain a therapeutic challenge despite the development of numerous treatment strategies. The phosphatidylinositol-3 kinase (PI3K)/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway plays a central role in regulating many cellular functions, including cell cycle, proliferation, quiescence, and longevity. Therefore, dysregulation of this pathway is a characteristic feature of carcinogenesis. Increased activation of PI3K/Akt/mTOR signaling enhances proliferation, growth, and resistance to chemo- and immunotherapy in cancer cells. Overactivation of the pathway has been found in various types of cancer, including acute and chronic leukemia. Inhibitors of the PI3K/Akt/mTOR pathway have been used in leukemia treatment since 2014, and some of them have improved treatment outcomes in clinical trials. Recently, new inhibitors of PI3K/Akt/mTOR signaling have been developed and tested both in preclinical and clinical models. In this review, we outline the role of the PI3K/Akt/mTOR signaling pathway in blood malignancies’ cells and gather information on the inhibitors of this pathway that might provide a novel therapeutic opportunity against leukemia.
... Loss or inhibition of MYC leads to exaggerated reliance on FAO as an energy source in several cell and tissue models (Graves et al., 2012;Zirath et al., 2013;Edmunds et al., 2014;2016). Finally, one canonical target of MYC is nucleotide metabolism, and MYC directly binds the regulatory regions of many genes encoding enzymes involved in purine and pyrimidine nucleotide biosynthesis (Liu et al., 2008). Moreover, MYC upregulates pathways such as de novo serine synthesis and one-carbon metabolism that support nucleotide biosynthesis (Sun et al., 2015). ...
... Most transcriptional programs driven by mt-ISR have been attributed to the transcription factor ATF4 (Quirós et al., 2017). However, very similar changes occur upon upregulation of MYC (Liu et al., 2008;Sun et al., 2015), which frequently accompanies mt-ISR (Table 2). Moreover, these two transcription factors share a high proportion of overlapping DNA-binding sites (Tameire et al., 2019). ...
The mitochondrion is a major hub of cellular metabolism and involved directly or indirectly in almost all biological processes of the cell. In mitochondrial diseases, compromised respiratory electron transfer and oxidative phosphorylation (OXPHOS) lead to compensatory rewiring of metabolism with resemblance to the Warburg-like metabolic state of cancer cells. The transcription factor MYC (or c-MYC) is a major regulator of metabolic rewiring in cancer, stimulating glycolysis, nucleotide biosynthesis, and glutamine utilization, which are known or predicted to be affected also in mitochondrial diseases. Albeit not widely acknowledged thus far, several cell and mouse models of mitochondrial disease show upregulation of MYC and/or its typical transcriptional signatures. Moreover, gene expression and metabolite-level changes associated with mitochondrial integrated stress response (mt-ISR) show remarkable overlap with those of MYC overexpression. In addition to being a metabolic regulator, MYC promotes cellular proliferation and modifies the cell cycle kinetics and, especially at high expression levels, promotes replication stress and genomic instability, and sensitizes cells to apoptosis. Because cell proliferation requires energy and doubling of the cellular biomass, replicating cells should be particularly sensitive to defective OXPHOS. On the other hand, OXPHOS-defective replicating cells are predicted to be especially vulnerable to high levels of MYC as it facilitates evasion of metabolic checkpoints and accelerates cell cycle progression. Indeed, a few recent studies demonstrate cell cycle defects and nuclear DNA damage in OXPHOS deficiency. Here, we give an overview of key mitochondria-dependent metabolic pathways known to be regulated by MYC, review the current literature on MYC expression in mitochondrial diseases, and speculate how its upregulation may be triggered by OXPHOS deficiency and what implications this has for the pathogenesis of these diseases.
... These results are in line with those of a previous study that used EBNA2 that was C-terminally fused to an estrogen receptor; EBNA2 ablation by 4-hydrohytamoxifen depletion decreased IMPDH2 gene expression in LCLs (24). EBNA2 induces the MYC gene (41), which is a transcriptional activator of IMPDH2 (25,42). The expression levels of IMPDH2 in primary lymphocytes and lymphomas are strongly correlated with those of MYC but not EBNA2 ( Fig. 2L; Fig. S2D). ...
EBV infections cause nucleolar enlargement via the induction of IMPDH2, which are essential for B cell growth transformation by EBV. Although the significance of IMPDH2 induction and nuclear hypertrophy in the tumorigenesis of glioblastoma has been reported, EBV infection brings about the change quickly by using its transcriptional cofactor, EBNA2, and MYC. Moreover, we present here, for the novel, basic evidence that an IMPDH2 inhibitor, namely, MPA or MMF, can be used for EBV-positive posttransplant lymphoproliferative disorder (PTLD).
... The Ras/Raf/MAPK pathway regulates many other pathways, such as the phosphatidylinositol kinase (PI3K-Akt-mTOR) pathway (reviewed by 23,24 , and induces phosphorylation and stabilization of the transcription factor Myc. The final targets of these pathways, including Myc, are connected to energy production (glycolysis and glutaminolysis), anabolic reactions 25 , the expression of glycolytic enzymes, activation of reductive carboxylation of α-ketoglutarate, and the production of citrate for fatty acid synthesis and lipogenesis (reviewed in 23,24,26 . ...
Metabolomics has proven to be an important omics approach to understand the molecular pathways underlying the tumour phenotype and to identify new clinically useful markers. The literature on cancer has illustrated the potential of this approach as a diagnostic and prognostic tool. The present study aimed to analyse the plasma metabolic profile of patients with oral squamous cell carcinoma (OSCC) and controls and to compare patients with metastatic and primary tumours at different stages and subsites using nuclear magnetic resonance and mass spectrometry. To our knowledge, this is the only report that compared patients at different stages and subsites and replicates collected in diverse institutions at different times using these methodologies. Our results showed a plasma metabolic OSCC profile suggestive of abnormal ketogenesis, lipogenesis and energy metabolism, which is already present in early phases but is more evident in advanced stages of the disease. Reduced levels of several metabolites were also associated with an unfavorable prognosis. The observed metabolomic alterations may contribute to inflammation, immune response inhibition and tumour growth, and may be explained by four nonexclusive views—differential synthesis, uptake, release, and degradation of metabolites. The interpretation that assimilates these views is the cross talk between neoplastic and normal cells in the tumour microenvironment or in more distant anatomical sites, connected by biofluids, signalling molecules and vesicles. Additional population samples to evaluate the details of these molecular processes may lead to the discovery of new biomarkers and novel strategies for OSCC prevention and treatment.
... Different transcription factors can produce nucleotides at the level of gene expression [24]. For instance, the transcription factor c-Myc controls nucleotide production by increasing the expression of many nucleotides [25,26]. Thymidylate synthase (TS), IMPDH1, and IMPDH2, and other nucleotide biosynthesis enzymes can be expressed more frequently when lncRNA upregulated c-Myc [27,28]. ...
... Transcription factors tightly regulate nucleotide metabolic pathways. The most researched is the transcription factor c-Myc, which binds to numerous significant genes in the nucleotide metabolic pathway and directly controls key metabolic enzymes, including CAD and IMPDH [25,31]. We have used bioinformatics to predict 10 transcription factors, including c-Myc, that function as UCA1 to regulate IMPDH1 and IMPDH2, since the involvement of other transcription factors in nucleotide metabolism has received less attention. ...
Metabolic dysregulation has been identified as one of the hallmarks of cancer biology. Based on metabolic heterogeneity between bladder cancer tissues and adjacent tissues, we discovered several potential driving factors for the bladder cancer occurrence and development. Metabolic genomics showed purine metabolism pathway was mainly accumulated in bladder cancer. Long noncoding RNA urothelial carcinoma-associated 1 (LncRNA UCA1) is a potential tumor biomarker for bladder cancer diagnosis and prognosis, and it increases bladder cancer cell proliferation, migration, and invasion via the glycolysis pathway. However, whether UCA1 plays a role in purine metabolism in bladder cancer is unknown. Our findings showed that UCA1 could increase the transcription activity of guanine nucleotide de novo synthesis rate limiting enzyme inosine monophosphate dehydrogenase 1 (IMPDH1) and inosine monophosphate dehydrogenase 2 (IMPDH2), triggering in guanine nucleotide metabolic reprogramming. This process was achieved by UCA1 recruiting the transcription factor TWIST1 which binds to the IMPDH1and IMPDH2 promoter region. Increased guanine nucleotide synthesis pathway products stimulate RNA polymerase-dependent production of pre-ribosomal RNA and GTPase activity in bladder cancer cells, hence increasing bladder cancer cell proliferation, migration, and invasion. We have demonstrated that UCA1 regulates IMPDH1/2-mediated guanine nucleotide production via TWIST1, providing additional evidence of metabolic reprogramming.
... In addition, scMSGL detected relationships between OTX2 and metabolic genes PAICS and PPAT in Group 3 tumors. These genes related to the human purine biosynthesis pathways have been previously reported to be induced by MYC [53]. This confirms that OTX2 is functionally cooperating with MYC to regulate gene expression in medulloblastoma [52,54]. ...
Background
Characterizing the topology of gene regulatory networks (GRNs) is a fundamental problem in systems biology. The advent of single cell technologies has made it possible to construct GRNs at finer resolutions than bulk and microarray datasets. However, cellular heterogeneity and sparsity of the single cell datasets render void the application of regular Gaussian assumptions for constructing GRNs. Additionally, most GRN reconstruction approaches estimate a single network for the entire data. This could cause potential loss of information when single cell datasets are generated from multiple treatment conditions/disease states.
Results
To better characterize single cell GRNs under different but related conditions, we propose the joint estimation of multiple networks using multiple signed graph learning (scMSGL). The proposed method is based on recently developed graph signal processing (GSP) based graph learning, where GRNs and gene expressions are modeled as signed graphs and graph signals, respectively. scMSGL learns multiple GRNs by optimizing the total variation of gene expressions with respect to GRNs while ensuring that the learned GRNs are similar to each other through regularization with respect to a learned signed consensus graph. We further kernelize scMSGL with the kernel selected to suit the structure of single cell data.
Conclusions
scMSGL is shown to have superior performance over existing state of the art methods in GRN recovery on simulated datasets. Furthermore, scMSGL successfully identifies well-established regulators in a mouse embryonic stem cell differentiation study and a cancer clinical study of medulloblastoma.
... Although the precise intracellular concentrations of (d)NTPs vary widely based on cell type, cellular context and culture conditions, a review of over 600 published values estimates that cancer cells have, on average, 6-11-fold greater dNTP and 1.25-5-fold greater NTP concentrations than non-malignant proliferating cells 22 . Numerous well-known oncogenes have been shown to enforce hyperactive (d)NTP synthesis; for example, mutant KRAS 8,25 , PI3K 26 and MYC 27,28 , which are all frequent drivers of human cancer, promote the activity and expression of key de novo pathway enzymes and indirectly support de novo pathway flux by increasing cellular uptake of glucose and other nutrients to provide the required ATP, ribose and amino acids. Conversely, loss-of-function mutations or silencing of nucleotide catabolism enzymes, such as SAM domain and HD domain-containing 1 (SAMDH1), which converts dNTPs to deoxynucleosides, have been reported to increase nucleotide pools by preventing nucleotide degradation 29,30 . ...
... As mentioned above, flux through the pyrimidine de novo pathway is increased downstream of various oncogenic signalling pathways 8,18,26,28 . Downstream of PI3K or MAPK pathway activation, CAD activity is accelerated by its phosphorylation by S6K (on Ser1869) 23 or ERK (on Thr456) 138 , respectively. ...
Metabolic alterations are a key hallmark of cancer cells, and the augmented synthesis and use of nucleotide triphosphates is a critical and universal metabolic dependency of cancer cells across different cancer types and genetic backgrounds. Many of the aggressive behaviours of cancer cells, including uncontrolled proliferation, chemotherapy resistance, immune evasion and metastasis, rely heavily on augmented nucleotide metabolism. Furthermore, most of the known oncogenic drivers upregulate nucleotide biosynthetic capacity, suggesting that this phenotype is a prerequisite for cancer initiation and progression. Despite the wealth of data demonstrating the efficacy of nucleotide synthesis inhibitors in preclinical cancer models and the well-established clinical use of these drugs in certain cancer settings, the full potential of these agents remains unrealized. In this Review, we discuss recent studies that have generated mechanistic insights into the diverse biological roles of hyperactive cancer cell nucleotide metabolism. We explore opportunities for combination therapies that are highlighted by these recent advances and detail key questions that remain to be answered, with the goal of informing urgently warranted future studies.
