Browse
Submit Data
Databases
API
Help

Dataset Information

20 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Regulation of Nucleotide Metabolism with Nutrient-Sensing Nanodrugs for Cancer Therapy.

ABSTRACT: The continual growth of tumor cells requires considerable nutrient consumption. Methotrexate (MTX) is used to treat certain types of cancer by blocking the DNA and RNA productions through interfering one-carbon metabolism and de novo purine and pyrimidine synthesis. However, treatment of MTX may cause many serious adverse effects, which hamper its clinical application. Herein, the authors synthesize ferrous ions, histidine, and MTX assembled nanoparticles (FHM) to deliver MTX at tumor site and enhance the sensitivity of tumor cells to MTX with histidine catabolism. Furthermore, fasting-mimicking diet (FMD) is applied to intervene in the one-carbon metabolism and enhance the cytotoxicity of MTX. Meanwhile, FMD treatment can significantly augment the cellular uptake and tumor accumulation of FHM nanoparticles. Due to the triple inhibitions of the one-carbon metabolism, the proliferation of tumor cells is strongly disturbed, as which is highly replying on DNA and RNA production. Taken together, a 95% lower dose of MTX adopted in combined therapy significantly inhibits the growth of two types of murine tumors without evident systemic toxicity. This strategy may provide a promising nucleotide metabolism-based nanomedicine for cancer therapy.

SUBMITTER: Wang X

PROVIDER: S-EPMC9284143 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Nutrient sensor O-GlcNAc transferase controls cancer lipid metabolism via SREBP-1 regulation.

Project description:Elevated O-GlcNAcylation is associated with disease states such as diabetes and cancer. O-GlcNAc transferase (OGT) is elevated in multiple cancers and inhibition of this enzyme genetically or pharmacologically inhibits oncogenesis. Here we show that O-GlcNAcylation modulates lipid metabolism in cancer cells. OGT regulates expression of the master lipid regulator the transcription factor sterol regulatory element binding protein 1 (SREBP-1) and its transcriptional targets both in cancer and lipogenic tissue. OGT regulates SREBP-1 protein expression via AMP-activated protein kinase (AMPK). SREBP-1 is critical for OGT-mediated regulation of cell survival and of lipid synthesis, as overexpression of SREBP-1 rescues lipogenic defects associated with OGT suppression, and tumor growth in vitro and in vivo. These results unravel a previously unidentified link between O-GlcNAcylation, lipid metabolism and the regulation of SREBP-1 in cancer and suggests a crucial role for O-GlcNAc signaling in transducing nutritional state to regulate lipid metabolism.

| S-EPMC5814337 | biostudies-literature

SOD1 Phosphorylation by mTORC1 Couples Nutrient Sensing and Redox Regulation.

Project description:Nutrients are not only organic compounds fueling bioenergetics and biosynthesis, but also key chemical signals controlling growth and metabolism. Nutrients enormously impact the production of reactive oxygen species (ROS), which play essential roles in normal physiology and diseases. How nutrient signaling is integrated with redox regulation is an interesting, but not fully understood, question. Herein, we report that superoxide dismutase 1 (SOD1) is a conserved component of the mechanistic target of rapamycin complex 1 (mTORC1) nutrient signaling. mTORC1 regulates SOD1 activity through reversible phosphorylation at S39 in yeast and T40 in humans in response to nutrients, which moderates ROS level and prevents oxidative DNA damage. We further show that SOD1 activation enhances cancer cell survival and tumor formation in the ischemic tumor microenvironment and protects against the chemotherapeutic agent cisplatin. Collectively, these findings identify a conserved mechanism by which eukaryotes dynamically regulate redox homeostasis in response to changing nutrient conditions.

| S-EPMC6108545 | biostudies-literature

Nutrient-Delivery and Metabolism Reactivation Therapy for Melanoma

Project description:To fulfil the demands of rapid proliferation, tumour cells, including those in melanoma, undergo significant metabolic alterations, with some pathways being upregulated while others are downregulated. Suppression of hyperactivated metabolism has been proven to counteract tumour growth. However, whether the reactivation of inversely downregulated metabolic pathways has therapeutic effects remains unexplored. Here, we report a nutrient-based metabolic reactivation strategy for effective melanoma treatment. Briefly, L-tyrosine nanomicelles (MTyr-OANPs) were constructed for targeted supplementation of tyrosine to reactivate melanogenesis in melanoma cells. We found that reactivation of melanogenesis using MTyr-OANPs significantly impedes the proliferation of melanoma cells, primaryly through the inhibition of glycolysis. We discovered that reduced glycolysis was a consequence of pyruvate kinase activity inhibition by melanin intermediates indole-5,6-quinone. Furthermore, leaveraging melanin as a natural photothermal reagent for photothermal therapy (PTT), we demonstrated the complete eradication of tumours in B16F10 melanoma-bearing mice through treatment with MTyr-OANPs and PTT. To the best of our knowledge, this is the first study of metabolism activation-based tumour treatment, suggesting specific nutrients as potent activators of metabolic pathways.

2024-04-11 | GSE263479 | GEO

Regulation of mammalian nucleotide metabolism and biosynthesis.

Project description:Nucleotides are required for a wide variety of biological processes and are constantly synthesized de novo in all cells. When cells proliferate, increased nucleotide synthesis is necessary for DNA replication and for RNA production to support protein synthesis at different stages of the cell cycle, during which these events are regulated at multiple levels. Therefore the synthesis of the precursor nucleotides is also strongly regulated at multiple levels. Nucleotide synthesis is an energy intensive process that uses multiple metabolic pathways across different cell compartments and several sources of carbon and nitrogen. The processes are regulated at the transcription level by a set of master transcription factors but also at the enzyme level by allosteric regulation and feedback inhibition. Here we review the cellular demands of nucleotide biosynthesis, their metabolic pathways and mechanisms of regulation during the cell cycle. The use of stable isotope tracers for delineating the biosynthetic routes of the multiple intersecting pathways and how these are quantitatively controlled under different conditions is also highlighted. Moreover, the importance of nucleotide synthesis for cell viability is discussed and how this may lead to potential new approaches to drug development in diseases such as cancer.

| S-EPMC4344498 | biostudies-literature

Chaperone dependent coordination of nutrient sensing and energy metabolism by mTORC2

Project description:mTORC2 senses nutrients and coordinates substrate metabolism and macromolecule synthesis program with the availability of external nutrient availability. Knockdown of mTORC2 components and its chaperone partners impairs both nutrient sensing and downstrem metabolism/growth programs.

2020-01-23 | GSE93948 | GEO

The SLC transporter in nutrient and metabolic sensing, regulation, and drug development.

Project description:The prevalence of metabolic diseases is growing worldwide. Accumulating evidence suggests that solute carrier (SLC) transporters contribute to the etiology of various metabolic diseases. Consistent with metabolic characteristics, the top five organs in which SLC transporters are highly expressed are the kidney, brain, liver, gut, and heart. We aim to understand the molecular mechanisms of important SLC transporter-mediated physiological processes and their potentials as drug targets. SLC transporters serve as 'metabolic gate' of cells and mediate the transport of a wide range of essential nutrients and metabolites such as glucose, amino acids, vitamins, neurotransmitters, and inorganic/metal ions. Gene-modified animal models have demonstrated that SLC transporters participate in many important physiological functions including nutrient supply, metabolic transformation, energy homeostasis, tissue development, oxidative stress, host defense, and neurological regulation. Furthermore, the human genomic studies have identified that SLC transporters are susceptible or causative genes in various diseases like cancer, metabolic disease, cardiovascular disease, immunological disorders, and neurological dysfunction. Importantly, a number of SLC transporters have been successfully targeted for drug developments. This review will focus on the current understanding of SLCs in regulating physiology, nutrient sensing and uptake, and risk of diseases.

| S-EPMC6359923 | biostudies-literature

Regulation of Polyamine Metabolism by Curcumin for Cancer Prevention and Therapy.

Project description:Curcumin (diferuloylmethane), the natural polyphenol responsible for the characteristic yellow pigment of the spice turmeric (Curcuma longa), is traditionally known for its antioxidant, anti-inflammatory, and anticarcinogenic properties. Capable of affecting the initiation, promotion, and progression of carcinogenesis through multiple mechanisms, curcumin has potential utility for both chemoprevention and chemotherapy. In human cancer cell lines, curcumin has been shown to decrease ornithine decarboxylase (ODC) activity, a rate-limiting enzyme in polyamine biosynthesis that is frequently upregulated in cancer and other rapidly proliferating tissues. Numerous studies have demonstrated that pretreatment with curcumin can abrogate carcinogen-induced ODC activity and tumor development in rodent tumorigenesis models targeting various organs. This review summarizes the results of curcumin exposure with regard to the modulation of polyamine metabolism and discusses the potential utility of this natural compound in conjunction with the exploitation of dysregulated polyamine metabolism in chemopreventive and chemotherapeutic settings.

| S-EPMC5753667 | biostudies-literature

Expression, regulation and putative nutrient-sensing function of taste GPCRs in the heart.

Project description:G protein-coupled receptors (GPCRs) are critical for cardiovascular physiology. Cardiac cells express >100 nonchemosensory GPCRs, indicating that important physiological and potential therapeutic targets remain to be discovered. Moreover, there is a growing appreciation that members of the large, distinct taste and odorant GPCR families have specific functions in tissues beyond the oronasal cavity, including in the brain, gastrointestinal tract and respiratory system. To date, these chemosensory GPCRs have not been systematically studied in the heart. We performed RT-qPCR taste receptor screens in rodent and human heart tissues that revealed discrete subsets of type 2 taste receptors (TAS2/Tas2) as well as Tas1r1 and Tas1r3 (comprising the umami receptor) are expressed. These taste GPCRs are present in cultured cardiac myocytes and fibroblasts, and by in situ hybridization can be visualized across the myocardium in isolated cardiac cells. Tas1r1 gene-targeted mice (Tas1r1(Cre)/Rosa26(tdRFP)) strikingly recapitulated these data. In vivo taste receptor expression levels were developmentally regulated in the postnatal period. Intriguingly, several Tas2rs were upregulated in cultured rat myocytes and in mouse heart in vivo following starvation. The discovery of taste GPCRs in the heart opens an exciting new field of cardiac research. We predict that these taste receptors may function as nutrient sensors in the heart.

| S-EPMC3655793 | biostudies-literature

Nutrient transporters: connecting cancer metabolism to therapeutic opportunities.

Project description:Cancer cells rely on certain extracellular nutrients to sustain their metabolism and growth. Solute carrier (SLC) transporters enable cells to acquire extracellular nutrients or shuttle intracellular nutrients across organelles. However, the function of many SLC transporters in cancer is unknown. Determining the key SLC transporters promoting cancer growth could reveal important therapeutic opportunities. Here we summarize recent findings and knowledge gaps on SLC transporters in cancer. We highlight existing inhibitors for studying these transporters, clinical trials on treating cancer by blocking transporters, and compensatory transporters used by cancer cells to evade treatment. We propose targeting transporters simultaneously or in combination with targeted therapy or immunotherapy as alternative strategies for effective cancer therapy.

| S-EPMC10266237 | biostudies-literature

M2 pyruvate kinase provides a mechanism for nutrient sensing and regulation of cell proliferation.

Project description:We show that the M2 isoform of pyruvate kinase (M2PYK) exists in equilibrium between monomers and tetramers regulated by allosteric binding of naturally occurring small-molecule metabolites. Phenylalanine stabilizes an inactive T-state tetrameric conformer and inhibits M2PYK with an IC50 value of 0.24 mM, whereas thyroid hormone (triiodo-L-thyronine, T3) stabilizes an inactive monomeric form of M2PYK with an IC50 of 78 nM. The allosteric activator fructose-1,6-bisphosphate [F16BP, AC50 (concentration that gives 50% activation) of 7 μM] shifts the equilibrium to the tetrameric active R-state, which has a similar activity to that of the constitutively fully active isoform M1PYK. Proliferation assays using HCT-116 cells showed that addition of inhibitors phenylalanine and T3 both increased cell proliferation, whereas addition of the activator F16BP reduced proliferation. F16BP abrogates the inhibitory effect of both phenylalanine and T3, highlighting a dominant role of M2PYK allosteric activation in the regulation of cancer proliferation. X-ray structures show constitutively fully active M1PYK and F16BP-bound M2PYK in an R-state conformation with a lysine at the dimer-interface acting as a peg in a hole, locking the active tetramer conformation. Binding of phenylalanine in an allosteric pocket induces a 13° rotation of the protomers, destroying the peg-in-hole R-state interface. This distinct T-state tetramer is stabilized by flipped out Trp/Arg side chains that stack across the dimer interface. X-ray structures and biophysical binding data of M2PYK complexes explain how, at a molecular level, fluctuations in concentrations of amino acids, thyroid hormone, and glucose metabolites switch M2PYK on and off to provide the cell with a nutrient sensing and growth signaling mechanism.

| S-EPMC3625322 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data