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The de novo pyrimidine and purine synthesis pathways. (A) Schematic of the de novo pyrimidine synthesis pathway. Pyrimidine synthesis enzymes: CAD: Carbamoyl-Phosphate Synthetase 2, Aspartate Transcarbamylase, And Dihydroorotase; DHODH: Dihydroorotate Dehydrogenase; UMPS: Uridine Monophosphate Synthetase. (B) Schematic of the de novo and purine salvage pathways. Purine synthesis enzymes: PPAT: phosphoribosyl pyrophosphate amidotransferase; GART: Glycinamide Ribonucleotide Transformylase; PFAS: Phosphoribosylformylglycinamidine Synthase; PAICS: Phosphoribosylaminoimidazole Carboxylase And Phosphoribosylamino-imidazolesuccinocarboxamide Synthase; ADSL: Adenylosuccinate Lyase; ATIC: 5-Aminoimidazole-4-Carboxamide Ribonucleotide Formyltransferase; IMPDH: Inosine Monophosphate Dehydrogenase; GMPS: Guanine Monophosphate Synthase; ADSS: Adenylosuccinate Synthase; HPRT: hypoxanthine phosphoribosyltransferase; APRT: adenine phosphoribosyltransferase.
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Cancer cells exhibit a dynamic metabolic landscape and require a sufficient supply of nucleotides and other macromolecules to grow and proliferate. To meet the metabolic requirements for cell growth, cancer cells must stimulate de novo nucleotide synthesis to obtain adequate nucleotide pools to support nucleic acid and protein synthesis along with...
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Cancer cells have a characteristic metabolism, mostly caused by alterations in signal transduction networks rather than mutations in metabolic enzymes. For metabolic drugs to be cancer-selective, signaling alterations need to be identified that confer a druggable vulnerability. Here, we demonstrate that many tumor cells with an acquired cancer drug...
Uncontrolled proliferation and altered metabolic reprogramming are hallmarks of cancer. Active glycolysis and glutaminolysis are characteristic features of these hallmarks and required for tumorigenesis. A fine balance between cancer metabolism and autophagy is a prerequisite of homeostasis within cancer cells. Here we show that glutamate pyruvate...
Citations
... 9 Once ZMP is formed, NTPs (ribonucleoside triphosphates) produced de novo can be employed for the synthesis of certain RNA. 10 Various studies on the mechanism conrmed that the transcription of such genes has a signicant effect on the endurance enhancement by increasing the activity of transcriptional regulators at a genetic level and enhancing the expression of genes in skeletal muscle. 11,12 As a result, doping with the substance AICAR was prohibited by the World Anti-Doping Agency (WADA) 13 in 2009, and its misuse was classied via metabolic regulators aer three years. ...
Objectives: AICAR (5-amino-4-imidazolecarboxyamide ribonucleoside) was reported as the first pharmacological AMPK (adenosine 5′-monophosphate (AMP)-activated protein kinase) activator, and it has been confirmed to exhibit a significant endurance enhancement effect and prohibited for doping by the World Anti-Doping Agency. Due to the fact that the human body can produce such substances, in order to ensure fairness in sports competition, methods for rapid detection and multi-type identification of AICAR drugs taken orally should be established. Methods: to assess AICAR levels, a new rapid, sensitive, efficient, and selective method was reported for the quantitative detection of AICAR in urine using LC-MS/MS. The method was validated for quantitative purposes based on the elemental selectivity, intra- (1.0–15.6%) and inter-day precision (1.3–16.3%), accuracy (99.9–112.8%), matrix effects (88.9–103.6%), recovery (87.4–106.5%), and stability at four different concentrations. The calibration curve was linear over a wide concentration range of 10–10,000 ng mL⁻¹ with a high coefficient of determination (R² > 0.998). The limit of detection (LOD) and limit of quantification (LOQ) for the experiment were determined to be 1 and 10 ng mL⁻¹, respectively. Simultaneously, metabolomics analysis was used to obtain the metabolic fingerprint of different populations and biomarkers to distinguish administration cases through partial least squares discriminant analysis (PLS-DA) and a receiver operating characteristic (ROC) curve. Results: the method enables easy quantitation for LC-MS/MS analysis with the best recovery yield maintained, and the method was applied to 122 Asian biological samples with an average concentration of 1310.5 ± 1031.4 ng mL⁻¹. Through drug metabolism research, 734 and 294 variables were extracted for data analysis respectively in the positive and negative ion modes, and more than 100 metabolites with significant up- and down-regulation were found after the test. Conclusions: this research developed a fast, precise, effective, and specific approach for the qualitative and quantitative identification of AICAR in urine. Meanwhile, administration metabolism studies found that there were significant changes in AICAR levels and other compounds, such as PC types PC(18:1/16:0), PC(16:0/18:0), and PC(16:0/16:0), PE types PE(18:0/20:4), and LPE-type 18:1, which could better distinguish samples before and after AICAR administration. The analysis provides a multi-perspective reference for WADA to determine a positive criterion.
... Nucleotides serve as monomeric units of DNA and RNA [130]. In tumors, de novo synthesis of these molecules is commonly exacerbated to sustain unlimited cell growth and proliferation [131]. This process is supported by different metabolic mechanisms, including the glucose-dependent PPP. ...
Aberrant activation of the PI3K/Akt pathway commonly occurs in cancers and correlates with multiple aspects of malignant progression. In particular, recent evidence suggests that the PI3K/Akt signaling plays a fundamental role in promoting the so-called aerobic glycolysis or Warburg effect, by phosphorylating different nutrient transporters and metabolic enzymes, such as GLUT1, HK2, PFKB3/4 and PKM2, and by regulating various molecular networks and proteins, including mTORC1, GSK3, FOXO transcription factors, MYC and HIF-1α. This leads to a profound reprogramming of cancer metabolism, also impacting on pentose phosphate pathway, mitochondrial oxidative phosphorylation, de novo lipid synthesis and redox homeostasis and thereby allowing the fulfillment of both the catabolic and anabolic demands of tumor cells. The present review discusses the interactions between the PI3K/Akt cascade and its metabolic targets, focusing on their possible therapeutic implications.
... The unexpected pattern of hypoxanthine in our targeted metabolomic analysis of a human cohort comprised of people with HU and gout prompted us to examine the underlying mechanisms regulating urate biosynthesis in the liver. It has long been established that urate can be generated from DNPB and the purine nucleotide salvage process 8 , but the contributions of these two pathways to HU are less clear 33 , especially purine salvage pathway 34 . The majority of HU people with endogenous urate overproduction appear to be due to the salvage pathway 8 . ...
Dyslipidemia affects approximately half of all people with gout, and prior Mendelian randomization analysis suggested a causal role for elevated triglycerides in hyperuricemia (HU), but the underlying mechanisms remain elusive. We hypothesize that dyslipidemia promotes hepatic urate biosynthesis in HU and gout and fatty acid (FA) oxidation (FAO) drives this process. Here we developed a targeted metabolomics to quantify major metabolites in purine metabolic pathway in the sera of a human cohort with HU, gout, and normaluricemic controls. We found that the levels of major purine metabolites and multiple FAs were significantly elevated in HU and gout, compared to normouricemic controls, whereas hypoxathine showed opposite trend. Furthermore, the levels of multiple serum FAs were positively correlated with urate, xanthine, and inosine but negatively with hypoxanthine, which was also observed in a murine model of high-fat diet-induced HU. Using a stable isotope labeled metabolic flux assay, we discovered that exogenous hypoxanthine plays a key role in urate synthesis. Moreover, FAO-induced hypoxia-inducible factor 1 alpha (HIF-1α) activation upregulated 5'-nucleotidase II (NT5C2) and xanthine dehydrogenase (XDH) levels to facilitate hypoxanthine uptake from blood to liver and activation of urate biosynthesis. Our findings was further supported by data in human hepatocytes and 50 paired serum and liver tissues from liver transplant donors.Together, this study uncovers a mechanism by which FAO promotes hepatic urate synthesis by activating HIF-1α-NT5C2/XDH pathways, directly linking lipid metabolism to HU.
... The studies have shown that conditional deletion of RRM1 in Ewing sarcoma cells causes the increase in expression of genes like c-Jun and c-Fos that hinder tumor growth and progression (Croushore et al., 2023). An increase in nucleotide biosynthesis in cancerous cells is also one of the factors responsible for increased cell proliferation (Villa et al., 2019). The study has shown that CRISPR-mediated depletion of ubiquitin-specific peptidase 29 (USP29) leads to the disruption of intermediates accountable for involvement in glycolysis and nucleotide biosynthesis in neuroblastoma cell lines (Chandrasekaran et al., 2021). ...
The discovery of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) technology has revolutionized field of cancer treatment. This review explores usage of CRISPR/Cas9 for editing and investigating genes involved in human carcinogenesis. It provides insights into the development of CRISPR as a genetic tool. Also, it explores recent developments and tools available in designing CRISPR/Cas9 systems for targeting oncogenic genes for cancer treatment. Further, we delve into an overview of cancer biology, highlighting key genetic alterations and signaling pathways whose deletion prevents malignancies. This fundamental knowledge enables a deeper understanding of how CRISPR/Cas9 can be tailored to address specific genetic aberrations and offer personalized therapeutic approaches. In this review, we showcase studies and preclinical trials that show the utility of CRISPR/Cas9 in disrupting oncogenic targets, modulating tumor microenvironment and increasing the efficiency of available anti treatments. It also provides insight into the use of CRISPR high throughput screens for cancer biomarker identifications and CRISPR based screening for drug discovery. In conclusion, this review offers an overview of exciting developments in engineering CRISPR/Cas9 therapeutics for cancer treatment and highlights the transformative potential of CRISPR for innovation and effective cancer treatments.
... Since SINE RNAs robustly accumulate early during malignant cellular transformation (37) and de novo purine synthesis contributes to the proliferation of cancer cells (38), we speculate that these DAMPs could be sensed intrinsically by epithelial-derived NLRC4 leading to a robust immune response. Finally, we show that the loss of NLRC4 expression in patient tumor tissues may be due to the presence of LPS (expressed by gram-negative bacteria) which specifically abolished NLRC4 expression at the transcriptional level but no other NLR-family members in human primary cells. ...
The immune system can control cancer progression. However, even though some innate immune sensors of cellular stress are expressed intrinsically in epithelial cells, their potential role in cancer aggressiveness and subsequent overall survival in humans is mainly unknown. Here, we show that NLR family CARD Domain Containing 4 (NLRC4) is downregulated in epithelial tumor cells of colorectal cancer (CRC) patients by using spatial tissue imaging. Strikingly, only the loss of tumor NLRC4 but not stromal is associated with poor immune infiltration (mainly dendritic and CD4+/CD8+ T cells) and accurately predicts progression to metastatic Stage IV and decrease of overall survival. By combining multi-omics approaches, we show that restoring NLRC4 expression in human colorectal cancer cells triggers a broad inflammasome-independent immune reprogramming consisting of Type-I IFN signaling genes and the release of chemokines and myeloid growth factors involved in the tumor infiltration and activation of dendritic cells (DCs) and T cells. Consistently, such reprogramming in cancer cells is sufficient to directly mature human DCs towards a Th1 antitumor immune response through IL-12 production in vitro. In multiple human carcinomas (colorectal, lung, and skin), we confirmed that NLRC4 expression in patient tumors is strongly associated with Type-I IFN genes, immune infiltrates and high microsatellite instability. Thus, we shed light on the epithelial innate immune sensor NLRC4 as a novel therapeutic target to promote an efficient antitumor immune response against the aggressiveness of various carcinomas.
... Nucleotide metabolism reprogramming cause cellular transformation and tumor progression. The production of pyrimidine nucleotides in organisms primarily occurs through two pathways: the de novo synthesis pathway and salvage synthesis pathway [7,8]. In rapidly proliferating cells, such as tumor cells and T-cells, pyrimidine nucleotides are continuously produced, predominantly through the de novo synthesis pathway [9][10][11]. ...
... It oxidizes dihydroorotic acid and converts it to orotate using glutamine as a substrate. Orotate is subsequently converted to UMP via the catalytic activity of UMP synthetase [7,12]. ...
Castration-resistant prostate cancer (CRPC) is an aggressive disease with poor prognosis, and there is an urgent need for more effective therapeutic targets to address this challenge. Here, we showed that dihydroorotate dehydrogenase (DHODH), an enzyme crucial in the pyrimidine biosynthesis pathway, is a promising therapeutic target for CRPC. The transcript levels of DHODH were significantly elevated in prostate tumors and were negatively correlated with the prognosis of patients with prostate cancer. DHODH inhibition effectively suppressed CRPC progression by blocking cell cycle progression and inducing apoptosis. Notably, treatment with DHODH inhibitor BAY2402234 activated androgen biosynthesis signaling in CRPC cells. However, the combination treatment with BAY2402234 and abiraterone decreased intratumoral testosterone levels and induced apoptosis, which inhibited the growth of CWR22Rv1 xenograft tumors and patient-derived xenograft organoids. Taken together, these results establish DHODH as a key player in CRPC and as a potential therapeutic target for advanced prostate cancer.
... [7][8][9][10][11][12] Pyrimidine nucleotides are essential for the biosynthesis of phospholipids, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), glycoproteins, and nucleotides. Resting or fully differentiated cells and rapidly growing cells like tumour cells and immune system-activated cells [13][14][15] fulfilled the pyrimidine requirement for their proliferation via the salvage and de novo biosynthesis pathways, respectively. ...
This study involves the design of novel thiadiazole derivatives as hDHODH inhibitors using various structure‐based approaches such as pharmacophore modelling, high‐throughput virtual screening (HTVS), prediction of ADMET parameters, docking and molecular dynamics (MD) studies. We used the validated co‐crystal structure of hDHODH to create the six‐feature pharmacophore model ADHRRR, which was validated by the Güner‐Henry scoring (GH score=0.81) approach, enrichment calculations (enrichment factor=51), area under the curve (0.93), receiving operating characteristic (ROC) curve (0.89), and ROC′s Boltzmann‐enhanced discrimination, known as BEDROC (α=8) (0.859), (α=20) (0.828), (α=160) (0.912). Pharmacophore model as a 3D search query was used for the screening of zinc database followed by docking investigations and energy calculation (Prime/MMGBSA). For the design of novel compounds, we selected the thiadiazole moiety as the central scaffold and various functional groups based on pharmacophoric characters and binding interactions. In docking study, designed compounds showed favourable interactions with Gln47 and Arg136 at the active site of the hDHODH enzyme, and optimal drug likeness properties for ADMET prediction study. Stability of enzyme‐ligand complex was validated by MD simulation study with RMSD, RMSF and RoG calculations. These findings suggested that novel thiadiazoles are potential candidates as hDHODH inhibitors and anticancer agents.
... These observations are particularly important since alterations in the PPP play an important role in metabolic reprogramming and HCC tumor development 44 . This proproliferative effect is mainly mediated through the production of ribose 5-phosphate (R5P) and its subsequent transformation into PRPP, which in turn is used as a precursor for nucleotide production 45 . In this context, while ChREBP's connection with enhanced pentose phosphate shunt was previously suggested, one important observation of our work was to identify ChREBP as a major player of glutaminolysis and de novo pyrimidine biosynthesis 46 . ...
Cancer cells integrate multiple biosynthetic demands to drive unrestricted proliferation. How these cellular processes crosstalk to fuel cancer cell growth is still not fully understood. Here, we uncover the mechanisms by which the transcription factor Carbohydrate responsive element binding protein (ChREBP) functions as an oncogene during hepatocellular carcinoma (HCC) development. Mechanistically, ChREBP triggers the expression of the PI3K regulatory subunit p85α, to sustain the activity of the pro-oncogenic PI3K/AKT signaling pathway in HCC. In parallel, increased ChREBP activity reroutes glucose and glutamine metabolic fluxes into fatty acid and nucleic acid synthesis to support PI3K/AKT-mediated HCC growth. Thus, HCC cells have a ChREBP-driven circuitry that ensures balanced coordination between PI3K/AKT signaling and appropriate cell anabolism to support HCC development. Finally, pharmacological inhibition of ChREBP by SBI-993 significantly suppresses in vivo HCC tumor growth. Overall, we show that targeting ChREBP with specific inhibitors provides an attractive therapeutic window for HCC treatment.
... In addition, it has been demonstrated that c-Myc plays a critical role in the maintenance of expression of PRPS2, PPAT, TrifGART, PAICS and IMPDH2 in melanoma cells (Mannava et al., 2008) and of PPAT, IMPDH1, IMPDH2 but not PAICS in a human lymphoma model cell line (Liu et al., 2008). Besides c-Myc, other oncogenes or tumor suppressors have also been shown in cancer cells to regulate the DNPNB pathway at the transcriptional level (Villa et al., 2019). More recently, in human lung cancer cells exhibiting a high level of the vestigial-like family member 3 (VGLL3), a cofactor for TEA domain transcription factors (TEADs), it has been demonstrated that TrifGART as well as PPAT (but not PAICS) expression is increased, but only GART gene knockdown reduces significantly cell proliferation (while PPAT gene knockdown has no impact), suggesting that VGLL3 stimulates the DNPNB pathway through TrifGART expression (Kawamura et al., 2022). ...
De novo purine nucleotide biosynthesis (DNPNB) consists of sequential reactions that are majorly conserved in living organisms. Several regulation events take place to maintain physiological concentrations of adenylate and guanylate nucleotides in cells and to fine-tune the production of purine nucleotides in response to changing cellular demands. Recent years have seen a renewed interest in the DNPNB enzymes, with some being highlighted as promising targets for therapeutic molecules. Herein, a review of two newly revealed modes of regulation of the DNPNB pathway has been carried out: i) the unprecedent allosteric regulation of one of the limiting enzymes of the pathway named inosine 5′-monophosphate dehydrogenase (IMPDH), and ii) the supramolecular assembly of DNPNB enzymes. Moreover, recent advances that revealed the therapeutic potential of DNPNB enzymes in bacteria could open the road for the pharmacological development of novel antibiotics.
... Therefore, modifying the chemotherapy regimen and shortening the treatment time have become urgent clinical issues to address [42][43][44][45]. Gemcitabine inhibits the activity of thymidylate synthase, thereby suppressing intracellular DNA synthesis [46][47][48]. With its long half-life, it can persist in tumor cells for an extended period to achieve an anti-tumor purpose [49][50]. ...
Objective: This study evaluated the efficacy and safety of the gemcitabine and oxaliplatin intrathoracic perfusion chemotherapy (IPCGOR) regimen combined with interleukin-2 (IL-2) for advanced non-small cell lung cancer (NSCLC).
Methods: We conducted a retrospective analysis of 460 advanced NSCLC patients from the Yunnan Province Early Cancer Diagnosis and Treatment Project (June 2020-October 2022), assessing the IPCGOR and IL-2 combination. Outcomes were measured based on RECIST 1.1 criteria, focusing on objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), median overall survival (MOS), and treatment safety.
Results: The treatment demonstrated an ORR of 67.4%, a DCR of 97.4%, an mPFS of 8.5 months, and an MOS of 12.5 months. 14 patients underwent successful surgery post-treatment. Common adverse reactions were manageable, with no treatment-related deaths reported.
Conclusion: The IPCGOR combined with IL-2 regimen shows promising efficacy and a tolerable safety profile for advanced NSCLC. These findings suggest its potential as a reference for treating advanced NSCLC. However, the study's retrospective nature and single-center design pose limitations. Future research should focus on prospective studies, randomized controlled trials, and long-term outcome assessments, particularly in diverse patient subgroups, to further validate and refine the clinical application of this regimen.
