Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress DOI Creative Commons
T. Brian, Peggy P. Hsu, Sidney Y. Vermeulen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Aug. 16, 2022

ABSTRACT Control of cellular identity requires coordination developmental programs with environmental factors such as nutrient availability, suggesting that modulating aspects metabolism could alter cell state along differentiation trajectories. Here we find nucleotide depletion and DNA replication stress are common drivers progression across a variety normal transformed hematopoietic systems. stress-induced transitions begin during S phase independent ATR/ATM checkpoint signaling, double-stranded break formation, changes in cycle length. In systems where is blocked by oncogenic transcription factor expression, leads to increased activity at primed regulatory loci expression lineage-appropriate maturation genes while progenitor TF still present. Altering the baseline manipulating cohort expressed redirects effect towards induction different set lineage-specific genes. The ability selectively activate contexts suggests general mechanism which can promote potentially therapeutically relevant transitions.

Language: Английский

A high throughput assay for phosphoribosylformylglycinamidine synthase DOI Creative Commons
Nandini Sharma, Yuka Otsuka, Louis Scampavia

et al.

SLAS DISCOVERY, Journal Year: 2025, Volume and Issue: unknown, P. 100212 - 100212

Published: Jan. 1, 2025

Metabolic reprogramming of purine biosynthesis is a hallmark cancer metabolism and represents critical vulnerability. The enzyme phosphoribosylformylglycinamidine synthase (PFAS) catalyzes the fourth step in de novo has been demonstrated to be prognostic for survival liver cancer. Despite importance this protein as drug target, there are no known specific inhibitors PFAS activity. Here, we describe new continuous, spectrophotometric assay domain that amenable high-throughput screening (HTS). This mechanism-based fluorescent makes use acid phosphatase substrate, 6,8-difluoro-4-methylumbelliferyl phosphate (DiFMUP). turnover DiFMUP with KM 108 ± 7 µM. After optimization miniaturization 1,536-well format, conducted pilot HTS using LOPAC1280 library. performed extremely well, an average Z´ 0.94 0.02, signal noise 5.01 0.06, excellent inter plate correlation, hit rate 1.18%. provides critically needed tool advance study enzymology will foundational discovery small molecule both functional probes basis development.

Language: Английский

Citations

0
Metabolic shifts in glioblastoma: unraveling altered pathways and exploring novel therapeutic avenues DOI
D.V. Malhotra, Reema Gabrani

Molecular Biology Reports, Journal Year: 2025, Volume and Issue: 52(1)

Published: Jan. 22, 2025

Language: Английский

Citations

0
Uracil Biomarker for Pyrimidine Metabolism in OSCC: Leveraging AI and Machine Learning for Improved Diagnosis DOI Creative Commons

Sesuraj Balasamy,

Dhanraj Ganapathy,

Deepak Nallaswamy

et al.

The Open Dentistry Journal, Journal Year: 2025, Volume and Issue: 19(1)

Published: Jan. 30, 2025

Language: Английский

Citations

0
KAT7-acetylated YBX1 promotes hepatocellular carcinoma proliferation by reprogramming nucleotide metabolism DOI Creative Commons
He Huang,

Longfei Ren,

Yongqiang Zhou

et al.

BMC Cancer, Journal Year: 2025, Volume and Issue: 25(1)

Published: Feb. 21, 2025

Language: Английский

Citations

0
Reprogramming of Thyroid Cancer Metabolism: from Mechanism to Therapeutic Strategy DOI Creative Commons

Yajuan Wan,

Guoqing Li,

Gaoyuan Cui

et al.

Molecular Cancer, Journal Year: 2025, Volume and Issue: 24(1)

Published: March 11, 2025

Abstract Thyroid cancer as one of the most prevalent malignancies endocrine system, has raised public concern and more research on its mechanism treatment. And metabolism-based therapies have advanced rapidly, for exclusive metabolic profiling thyroid cancer. In cells, plenty pathways are reprogrammed to accommodate tumor microenvironment. this review, we initiatively summarize recent progress in full-scale rewiring interconnection various metabolites. We also discuss efficacy prospect targeted detection well therapy. Comprehending characteristics roundly will be highly beneficial managing individual patients.

Language: Английский

Citations

0
Metabolomics: metabolic signatures in cancer biomarkers DOI
Chandramani Pathak, Foram U. Vaidya, Aafreen Ansari

et al.

Elsevier eBooks, Journal Year: 2025, Volume and Issue: unknown, P. 127 - 147

Published: Jan. 1, 2025

Language: Английский

Citations

0
De Novo Purine Metabolism is a Metabolic Vulnerability of Cancers with Low p16 Expression DOI Creative Commons
Naveen Kumar Tangudu, Raquel Buj, Hui Wang

et al.

Cancer Research Communications, Journal Year: 2024, Volume and Issue: 4(5), P. 1174 - 1188

Published: April 16, 2024

Abstract p16 is a tumor suppressor encoded by the CDKN2A gene whose expression lost in approximately 50% of all human cancers. In its canonical role, inhibits G1–S-phase cell cycle progression through suppression cyclin-dependent kinases. Interestingly, also has roles metabolic reprogramming, and we previously published that loss promotes nucleotide synthesis via pentose phosphate pathway. However, broader impact p16/CDKN2A on other pathways potential therapeutic targets remains unexplored. Using CRISPR knockout libraries isogenic mouse melanoma lines, determined several metabolism genes essential for survival cells with p16/CDKN2A. Consistently, many these are upregulated knockdown or endogenously low expression. We sensitive to multiple inhibitors de novo purine synthesis, including antifolates. Finally, tumors were more antifolate methotrexate vivo than control tumors. Together, our data provide evidence reevaluate utility drugs patients p16/CDKN2Alow as may window agents. Significance: Antimetabolites first chemotherapies, yet have failed clinic due toxicity poor patient selection. Our suggest provides kill cancer widely-used antifolates relatively little toxicity.

Language: Английский

Citations

3
Interplay between altered metabolism and DNA damage and repair in ovarian cancer DOI Creative Commons
Apoorva Uboveja, Katherine M. Aird

BioEssays, Journal Year: 2024, Volume and Issue: 46(8)

Published: June 14, 2024

Ovarian cancer is the most lethal gynecological malignancy and often associated with both DNA repair deficiency extensive metabolic reprogramming. While still emerging, interplay between these pathways can affect ovarian phenotypes, including therapeutic resistance to damaging agents that are standard-of-care for this tumor type. In review, we will discuss what currently known about cellular rewiring in may impact damage addition highlighting how specific proteins also promote changes. We relevant data from other cancers could be used inform strategies. Changes choice of mechanism adopted by a major factor promoting resistance. Therefore, reprogramming on mechanisms has clinical implications targeted combination therapies treatment devastating disease.

Language: Английский

Citations

3
Therapeutic Efficacy of Nanocarrier‐Mediated Inhalable Gene Transfection for Lung Cancer DOI
Poulami Sarkar,

M. Rizwan Sardar,

Olivia Sen

et al.

ChemistrySelect, Journal Year: 2024, Volume and Issue: 9(37)

Published: Oct. 1, 2024

Abstract Lung cancer is now the leading cause of cancer‐related mortality, eclipsing all other forms, and lung malignancies, non‐small cell (NSCLC) makes up around 85%. Recently, use vectors in gene therapy besides chemotherapy to treat malignancies brought on by mutations has gained prominence. Therapeutic molecule inhalation a direct approach lung‐targeted medication delivery with low nonspecific toxicity limited drug exposure. Treatment for immunotherapy can be aided inhalable nanomedicine through advanced mechanisms. Viral nonviral vectors, such as lipid‐based nanoparticles, polymeric inorganic have drawn lot interest their ability increase effects decrease side effects. Nanocarriers significant impact targeted delivery, bioavailability, stability, residence target areas. The inhaled pulmonary approach, when combined nanomedicine, will offer noninvasive successful way taking physiological properties lung. authors majorly used data from PubMed Google Scholar obtain relevant information required article. In general, this review concentrates usage various nanocarriers, which might serve an inspiration creation deployment more potent genetic treatment cancer.

Language: Английский

Citations

2
Human plasma-like medium facilitates metabolic tracing and enables upregulation of immune signaling pathways in glioblastoma explants DOI Creative Commons
Milan R. Savani, Mohamad El Shami, Lauren C. Gattie

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: May 31, 2023

Metabolism within the tumor microenvironment (TME) represents an increasing area of interest to understand glioma initiation and progression. Stable isotope tracing is a technique critical study metabolism. Cell culture models this disease are not routinely cultured under physiologically relevant nutrient conditions do retain cellular heterogeneity present in parental TME. Moreover, vivo, stable intracranial xenografts, gold standard for metabolic investigation, time consuming technically challenging. To provide insights into metabolism presence intact TME, we performed analysis patient-derived, heterocellular Surgically eXplanted Organoid (SXO) human plasma-like medium (HPLM). Glioma SXOs were established conventional media or transitioned HPLM. We evaluated SXO cytoarchitecture histology, then spatial transcriptomic profiling identify populations differential gene expression patterns. with 15N2-glutamine evaluate intracellular metabolite labeling HPLM constituents. Immune cells HPLM-cultured demonstrated increased transcription immune-related signatures, including innate immune, adaptive cytokine signaling programs. 15N enrichment from glutamine was observed metabolites diverse pathways, patterns over time. enable ex tractable investigations whole metabolism, developed approach conduct conditions. Under these conditions, maintained viability, composition, activity while exhibiting transcriptional

Language: Английский

Citations

5