Targeting E2F Sensitizes Prostate Cancer Cells to Drug-Induced Replication Stress by Promoting Unscheduled CDK1 Activity DOI Open Access
M. El Hamidi, Ainhoa Eriz,

Jone Mitxelena

et al.

Cancers, Journal Year: 2022, Volume and Issue: 14(19), P. 4952 - 4952

Published: Oct. 10, 2022

E2F1/E2F2 expression correlates with malignancy in prostate cancer (PCa), but its functional significance remains unresolved. To define the mechanisms governed by E2F PCa, we analyzed contribution of target genes to control genome integrity, and impact modulating activity on PCa progression. We show that silencing or inhibiting induces DNA damage during S phase potentiates 5-FU-induced replication stress cellular toxicity. Inhibition downregulates targets involved nucleotide biosynthesis (TK1, DCK, TYMS), whose is upregulated 5-FU. However, their enzymatic products failed rescue knockdown cells, suggesting additional for function. Interestingly, targeting cells reduced WEE1 resulted premature CDK1 activation phase. CDK1/CDK2 prevented induced loss, safeguard integrity restraining activity. Importantly, combined inhibition ATR boosted dramatically tumorigenic capacity xenografts. Collectively, combination drugs repair a promising strategy provoke catastrophic levels could be applied treatment.

Language: Английский

Metabolic reprogramming in cancer: Mechanisms and therapeutics DOI Creative Commons

Shiqi Nong,

Xiaoyue Han, Xiang Yu

et al.

MedComm, Journal Year: 2023, Volume and Issue: 4(2)

Published: March 27, 2023

Abstract Cancer cells characterized by uncontrolled growth and proliferation require altered metabolic processes to maintain this characteristic. Metabolic reprogramming is a process mediated various factors, including oncogenes, tumor suppressor genes, changes in tumor–host cell interactions, which help meet the needs of cancer anabolism promote development. dynamically variable, depending on type microenvironment, involves multiple pathways. These pathways have complex mechanisms involve coordination signaling molecules, proteins, enzymes, increases resistance traditional antitumor therapies. With development therapies, has been recognized as new therapeutic target for cells. Therefore, understanding how change can provide reference therapies treatment. Here, we systemically reviewed their alteration together with current regulation treatments other possible that are still under investigation. Continuous efforts needed further explore mechanism metabolism corresponding treatments.

Language: Английский

Citations

100
Regulation of nucleotide metabolism in cancers and immune disorders DOI Creative Commons
Eunüs S. Ali, Issam Ben‐Sahra

Trends in Cell Biology, Journal Year: 2023, Volume and Issue: 33(11), P. 950 - 966

Published: March 24, 2023

Language: Английский

Citations

46
Plant Foods and Their Bioactives as Dietary Enhancers for Colon Cancer Treatment with 5-Fluorouracil DOI
Zhongming Yang, Carlos L. Céspedes, Zhongguo Yang

et al.

Food Reviews International, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 50

Published: Jan. 4, 2025

Cancer is the world's second most common cause of death, with colon cancer (CC) ranking third in prevalence and cancer-related fatalities. CC originates or rectum influenced by genetic mutations, lifestyle, diet. Although chemotherapy, especially 5-fluorouracil (5-FU), fundamental to treatment has improved patient survival, its benefits are often limited significant side effects emerging drug resistance. Recently, plant-based foods have drawn interest research for their natural bioactive compounds relatively low toxicity. Certain plant not only exhibit anti-cancer activity but may also boost effectiveness 5-FU while reducing adverse effects. Despite evidence suggesting a synergistic effect between 5-FU, this area remains fragmented. This review consolidates current on including fruits, vegetables, legumes, tea bioactives treatment. Besides, it explores mechanisms through which these enhance efficacy reduce effects, evaluates clinical application prospects, identifies challenges future directions. comprehensive analysis aims provide scientific foundation integrated CC, highlighting potential enhancing chemotherapy associated toxicities.

Language: Английский

Citations

7
mTORC1 regulates the pyrimidine salvage pathway by controlling UCK2 turnover via the CTLH-WDR26 E3 ligase DOI Creative Commons
Brittany Q Pham, Sang Ah Yi, Alban Ordureau

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: 44(1), P. 115179 - 115179

Published: Jan. 1, 2025

Language: Английский

Citations

1
Six‐Membered Aromatic Nitrogen Heterocyclic Anti‐Tumor Agents: Synthesis and Applications DOI
Jiatong Li,

Ao Gu,

Xiao‐Mei Nong

et al.

The Chemical Record, Journal Year: 2023, Volume and Issue: 23(12)

Published: Nov. 27, 2023

Cancer stands as a serious malady, posing substantial risks to human well-being and survival. This underscores the paramount necessity explore investigate novel antitumor medications. Nitrogen-containing compounds, especially those derived from natural sources, form highly significant category of agents. Among these, agents with six-membered aromatic nitrogen heterocycles have consistently attracted attention chemists pharmacologists. Accordingly, we present comprehensive summary synthetic strategies clinical implications these compounds in this review. entails an in-depth analysis synthesis pathways for pyridine, quinoline, pyrimidine, quinazoline. Additionally, historical progression, targets, mechanisms action, effectiveness small molecule inhibitors possessing structural features.

Language: Английский

Citations

17
Interplay between mTOR and Purine Metabolism Enzymes and Its Relevant Role in Cancer DOI Open Access
S. Allegrini, Marcella Camici, Mercedes Garcia‐Gil

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(12), P. 6735 - 6735

Published: June 19, 2024

Tumor cells reprogram their metabolism to meet the increased demand for nucleotides and other molecules necessary growth proliferation. In fact, cancer are characterized by an "de novo" synthesis of purine nucleotides. Therefore, it is not surprising that specific enzymes targets drugs as antineoplastic agents, a better knowledge mechanisms underlying regulation would be great help in finding new therapeutic approaches. The mammalian target rapamycin (mTOR) signaling pathway, which often activated cells, promotes anabolic processes major regulator cell division. Among numerous effects exerted mTOR, noteworthy its empowerment nucleotides, accomplished supporting formation purinosomes, increasing availability precursors, such one-carbon formyl group, bicarbonate 5-phosphoribosyl-1-pyrophosphate. this review, we highlight connection between mitochondrial metabolism, bidirectional relation mTOR pathways.

Language: Английский

Citations

6
Targeting the DNA damage response and repair in cancer through nucleotide metabolism DOI Creative Commons
Thomas Helleday, Sean G. Rudd

Molecular Oncology, Journal Year: 2022, Volume and Issue: 16(21), P. 3792 - 3810

Published: May 18, 2022

The exploitation of the DNA damage response and repair proficiency cancer cells is an important anticancer strategy. replication are dependent upon supply deoxynucleoside triphosphate (dNTP) building blocks, which produced maintained by nucleotide metabolic pathways. Enzymes within these pathways can be promising targets to selectively induce toxic lesions in cells. These same also activate antimetabolites, group chemotherapies that disrupt both metabolism Thus, dNTP enzymes targeted refine use chemotherapeutics, many remain standard care common cancers. In this review article, we will discuss approaches exemplified MTH1, MTHFD2 SAMHD1. © 2022 Authors. Molecular Oncology published John Wiley & Sons Ltd on behalf Federation European Biochemical Societies.

Language: Английский

Citations

27
Integrative Analyses of Pyrimidine Salvage Pathway-Related Genes Revealing the Associations Between UPP1 and Tumor Microenvironment DOI Creative Commons
Yin Li,

Manling Jiang,

Yongqi Wei

et al.

Journal of Inflammation Research, Journal Year: 2024, Volume and Issue: Volume 17, P. 101 - 119

Published: Jan. 1, 2024

Background: The pyrimidine salvage pathway plays a critical role in tumor progression and patient outcomes. roles of pathway-related genes (PSPGs) cancer, however, are not fully understood. This study aims to depict the characteristics PSPGs across various cancers. Methods: An integrative pan-cancer analysis six (CDA, UCK1, UCK2, UCKL1, UPP1, UPP2) was conducted using TCGA data, single-cell RNA sequencing datasets, samples. Single-cell transcriptome RT-qPCR were used validate relation between UPP1 cytokines. Flow cytometry performed immune checkpoint regulation. correlation associated neutrophils (TAN) investigated validated by tissue microarrays (TMAs). Results: showed low mutation rates but significant copy number variations, particularly amplifications UCK2 DNA methylation patterns varied, with notable negative correlations gene expression UPP1. broadly up-regulated multiple cancers, clinical staging prognosis. Proteomic data further confirmed these findings. Functional revealed PSPGs' associations proliferation, metastasis, signaling pathways. strong microenvironment (TME), cytokines, checkpoints, cells. associations, highlighting UPP1's influence on cytokine In esophageal squamous cell carcinoma (ESCC), UPP1-high cells significantly immunosuppressive TME. Spatial TMAs that UPP1+ predominantly located at invasive margin closely neutrophils, correlating poorer Conclusion: Our depicted multi-dimensional view particular focus Targeting holds promise as potential strategy for cancer therapy. Keywords: pathways,

Language: Английский

Citations

5
A Brief Review on the Synthesis of 4H‐Chromene‐Embedded Heterocycles DOI

K. Nissi Sharon,

P. Padmaja,

Pedavenkatagari Narayana Reddy

et al.

ChemistrySelect, Journal Year: 2024, Volume and Issue: 9(27)

Published: July 12, 2024

Abstract Chromenes are an essential class of oxygen‐containing heterocyclic compounds with intriguing biological activity. It is important moiety for the discovery new drug candidates. naturally abundant as alkaloids, tocopherols, flavones, and anthocyanins. The incorporation 4 H ‐chromene, along various bioactive heterocycles such indole, pyrazole, kojic acid, pyran‐2‐one, quinoline, pyridine, pyrimidine, coumarin, sesamol, furan, uracil, benzoimidazole, benzotriazole, thiazole, isoxazole barbituric acid moieties, into a molecular scaffold has potential to combine properties both components. synergistic effect combining different moieties within ‐chromene nucleus results in formation valuable significant importance. This review summarizes synthetic techniques used preparing ‐chromene‐embedded heterocycles. common mechanisms key reactions significance method discussed.

Language: Английский

Citations

5
Non-canonical role of UCKL1 on ferroptosis defence in colorectal cancer DOI Creative Commons
Weili Wu, Yingying Zhao,

Baifu Qin

et al.

EBioMedicine, Journal Year: 2023, Volume and Issue: 93, P. 104650 - 104650

Published: June 19, 2023

Pyrimidine nucleotides fuel the growth of colorectal cancer (CRC), making their associated proteins potential targets for intervention. Uridine-Cytidine Kinase Like-1(UCKL1) is an enzyme involved in pyrimidine salvage pathway. It highly expressed multiple cancers. But function and underlying mechanism UCKL1 CRC are yet to study.Large-scale genomic analysis was performed search players related metabolism. The were examined by RNA interference coupled with vitro vivo assays. GSH/GSSG assay, NADP+ ROS, Lipid peroxidation assays check ferroptosis. Metabolomics analyses, sequencing, western blotting, rescue done reveal mechanisms UCKL1. Xenograft mouse model used examine therapeutic as a target combination other ferroptosis inducers.UCKL1 identified repress cells. CRC. regulated cells proliferation migration. Downregulation led enhanced tumour lipid peroxidation. Intriguingly, reduction-mediated not its role catalyzing uridine monophosphate (UMP) cytidine (CMP) synthesis. Instead, stabilized Nrf2, which turn promoted expression SLC7A11, classical repressor Moreover, downregulation sensitized GPX4 inhibitors vivo.Our study demonstrates that plays non-canonical repressing through UCKL1-Nrf2-SLC7A11 axis Combinatorial strategy targeting depletion application may serve new effective method treatment.This supported part fund from National Natural Science Foundation China (Grant No. 31970674 PY), Basic Applied Research Program Guangdong Province 2023A1515030245 KL), program Provincial Clinical Center Digestive Diseases (2020B1111170004), Key Discipline.

Language: Английский

Citations

13