Biomimetic Nanomedicine Targeting Orchestrated Metabolism Coupled with Regulatory Factors to Disrupt the Metabolic Plasticity of Breast Cancer

ACS Nano, Год журнала: 2024, Номер 18(5), С. 4360 - 4375

Опубликована: Янв. 26, 2024

Targeting nutrient metabolism has been proposed as an effective therapeutic strategy to combat breast cancer because of its high requirements. However, metabolic plasticity enables cells survive under unfavorable starvation conditions. The key mammalian target regulators rapamycin (mTOR) and hypoxia-inducible-factor-1 (HIF-1) tightly link the dynamic glutamine glucose maintain flux. Blocking flow also induces autophagy recycle nutrients in autophagosome, which exacerbates metastasis tumor progression. Compared other common cancers, is even more dependent on mTOR HIF-1 orchestrate network. Therefore, we develop a cascade-boosting integrated nanomedicine reprogram complementary coupled with cancer. Glucose oxidase efficiently consumes glucose, while delivery inside limits flux uncouples feedback regulation HIF-1. hydroxyl radical generated cascade blocks later phase without recycling. This targeting orchestrated can disrupt coordination amino acids, nucleotides, lipids, pathways tissues, effectively improving durable antitumor effect prognosis Overall, system provides viable address cellular efficient enzyme delivery.

Язык: Английский

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A traditional gynecological medicine inhibits ovarian cancer progression and eliminates cancer stem cells via the LRPPRC–OXPHOS axis

Journal of Translational Medicine, Год журнала: 2023, Номер 21(1)

Опубликована: Июль 26, 2023

Ovarian cancer (OC) is the most lethal malignant gynecological tumor type for which limited therapeutic targets and drugs are available. Enhanced mitochondrial oxidative phosphorylation (OXPHOS), enables cell growth, migration, stem maintenance, a critical driver of disease progression potential intervention target OC. However, current OXPHOS strategy mainly suppresses activity electron transport chain directly cannot effectively distinguish normal tissues from tissues, resulting in serious side effects efficacy.We screened natural product libraries to investigate anti-OC that OXPHOS. Additionally, LC-MS, qRT-PCR, western-blot, clonogenic assay, Immunohistochemistry, wound scratch xenograft model was applied evaluate anti-tumor mechanism small molecules obtained by screening OC.Gossypol acetic acid (GAA), widely used medicine, out drug library with function suppressing OC targeting leucine-rich pentatricopeptide repeat containing (LRPPRC) protein. Mechanically, LRPPRC promotes synthesis subunits binding RNAs encoded DNA. GAA binds induces rapid degradation ubiquitin-independent manner. overexpressed OC, highly correlated poor outcomes could promote phenotype cells vitro vivo. management inhibits clonal formation, maintenance vitro, subcutaneous graft growth vivo.Our study identified provided corresponding inhibitor OXPHOS-based therapy. complex via protein, supporting its utility as agent ovarian cancer.

Язык: Английский

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Recreating metabolic interactions of the tumour microenvironment

Trends in Endocrinology and Metabolism, Год журнала: 2024, Номер 35(6), С. 518 - 532

Опубликована: Янв. 10, 2024

Язык: Английский

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Transcriptomic analysis of iPSC-derived endothelium reveals adaptations to high altitude hypoxia in energy metabolism and inflammation

PLoS Genetics, Год журнала: 2025, Номер 21(2), С. e1011570 - e1011570

Опубликована: Фев. 10, 2025

Tibetan adaptation to high-altitude hypoxia remains a classic example of Darwinian selection in humans. Amongst populations, alleles the EPAS1 gene - whose protein product, HIF-2α, is central regulator response have repeatedly been shown carry some strongest signals positive However, selective sweep alone may only account for phenotypes that differentiate adapted populations from closely related lowlanders. Therefore, there pressing need functionally probe adaptive and their impact at both locus-specific genome-wide levels across cell types uncover full range beneficial traits. To this end, we established library induced pluripotent stem cells (iPSCs) derived Han Chinese individuals, robust model system allowing precise exploration allelic effects on transcriptional responses, differentiated them into vascular endothelium. Using system, focus first hypoxia-dependent enhancer (ENH5) contributes regulation investigate its Then, cast wider net, harness same experimental compare transcriptome find evidence angiogenesis, energy metabolism immune pathways differ between these two with different histories long-term residence high altitude. Coupled polygenic adaptations targeting pathways, results suggests observed differences were shaped by natural selection.

Язык: Английский

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Preclinical models of immune checkpoint inhibitors-related interstitial pneumonia for anti-PD1 tumor immunotherapy

Immunobiology, Год журнала: 2025, Номер 230(2), С. 152884 - 152884

Опубликована: Фев. 17, 2025

Immune-related adverse reactions (irAEs) are common after immune checkpoint inhibitor treatment, impacting the universality and continued use of immunotherapy. Currently, preclinical models to investigate mechanisms underlying these effects inadequate. This study aims develop both in vitro vivo irAEs advance basic research on reactions. For models, we designed two co-culture systems: "Lung epithelial cells-PBMC" conditional model "organoid-PBMCs" model. These involve culturing spheroids, patient-derived organoids isolating, expanding, co-culturing peripheral blood mononuclear cells (PBMCs). model, PD1 humanized mice were used establish a lung carcinoma situ offspring, with blocked checkpoints induce systemic inflammatory responses. Mice without PD-1 blockade served as control group. In organoid "lung cell-PBMC" compared group, PBMC+anti-PD1 group exhibited injury, demonstrated by worst activity, increased collagen deposition, elevated mRNA levels αSMA Vimentin, higher Fibronectin expression, factors (IL6, IL1β, MPO) culture supernatant (p < 0.05). also showed pulmonary inflammation, slower weight gain affected mice, more obvious interstitial thickening(Masson staining α-SMA immunofluorescence staining), IL17A alveolar lavage fluid serum. successfully developed using technology, conditioned mouse effectively reproducing injury offering valuable tools for irAE research.

Язык: Английский

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Iron affects the sphere-forming ability of ovarian cancer cells in non-adherent culture conditions

Frontiers in Cell and Developmental Biology, Год журнала: 2023, Номер 11

Опубликована: Ноя. 14, 2023

Introduction: Detachment from the extracellular matrix (ECM) is first step of metastatic cascade. It a regulated process involving interaction between tumor cells and microenvironment (TME). Iron key micronutrient within TME. Here, we explored role iron in ability ovarian cancer to successfully detach ECM. Methods: HEY PEO1 were grown 3D conditions. To mimic an rich TME, culture media supplemented with 100 μM Fe3+. Cell mortality was evaluated by cytofluorimetric assay. The invasive potential spheroids performed Matrigel documented images time-lapses. metabolism assessed analyzing expression CD71 FtH1, quantifying intracellular labile pool (LIP) through Calcein-AM Ferroptosis mitochondrial reactive oxygen species (ROS) lipid peroxidation MitoSOX BODIPY-C11 assays, respectively. markers GPX4 VDAC2 measured Western blot. FtH1 knockdown using siRNA. Results: generate spheroids, prevent LIP accumulation upregulating FtH1. moderately increases only slightly reduced. PEO1upregulate results significantly diminished. import downregulating CD71, while strongly enhance it. Intracellular ROS drop down during 2D transition both cell lines, but more cells. Upon supplementation, continue without accumulating do not undergo ferroptosis. HEY, instead, accumulate LIP, ferroptosis attenuate their sphere-forming invasiveness. reduces generation although sensitizing them Discussion: reprogramming event spheroid An iron-rich environment impairs causes death sensitive A better understanding sensitivity could be useful develop effective treatments kill ECM-detached

Язык: Английский

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Beyond ENO1, emerging roles and targeting strategies of other enolases in cancers

Molecular Therapy — Oncolytics, Год журнала: 2023, Номер 31, С. 100750 - 100750

Опубликована: Ноя. 10, 2023

Язык: Английский

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Identification of a set of genes potentially responsible for resistance to ferroptosis in lung adenocarcinoma cancer stem cells

Cell Death and Disease, Год журнала: 2024, Номер 15(4)

Опубликована: Апрель 29, 2024

Scientific literature supports the evidence that cancer stem cells (CSCs) retain inside low reactive oxygen species (ROS) levels and are, therefore, less susceptible to cell death, including ferroptosis, a type of death dependent on iron-driven lipid peroxidation. A collection lung adenocarcinoma (LUAD) primary lines derived from malignant pleural effusions (MPEs) patients was used obtain 3D spheroids enriched for stem-like properties. We observed ferroptosis inducer RSL3 triggered peroxidation in LUAD when grown 2D conditions; however, conditions, all underwent phenotypic switch, exhibiting substantial resistance and, protection against ferroptotic death. Interestingly, this phenomenon reversed by disrupting growing them back adherence, supporting idea CSCs plasticity, which holds have dynamic ability transition between CSC state non-CSC state. Molecular analyses showed correlated with an increased expression antioxidant genes high proteins involved iron storage export, indicating oxidative stress availability initiation ferroptosis. Moreover, transcriptomic highlighted novel subset commonly modulated potentially capable driving LUAD-CSCs, thus allowing better understand mechanisms CSC-mediated drug tumors.

Язык: Английский

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Three-dimensional environment sensitizes pancreatic cancer cells to the anti-proliferative effect of budesonide by reprogramming energy metabolism

Journal of Experimental & Clinical Cancer Research, Год журнала: 2024, Номер 43(1)

Опубликована: Июнь 14, 2024

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is the most lethal cancer with an aggressive metastatic phenotype and very poor clinical prognosis. Interestingly, a lower occurrence of PDAC has been described in individuals severe long-standing asthma. Here we explored potential link between glucocorticoid (GC) budesonide, first-line therapy to treat Methods We tested effect budesonide classical GCs on morphology, proliferation, migration invasiveness patient-derived cells pancreatic cell lines, using 2D 3D cultures vitro. Furthermore, xenograft model was used investigate tumor growth vivo. Finally, combined genome-wide transcriptome analysis genetic pharmacological approaches explore mechanisms underlying activities different environmental conditions. Results found that culture settings, high micromolar concentrations reduced mesenchymal invasive/migrating features cells, without affecting proliferation or survival. This activity specific independent Glucocorticoid Receptor (GR). Conversely, more physiological environment, low nanomolar strongly GR-dependent manner. Accordingly, Mechanistically, demonstrated environment drives towards general metabolic reprogramming involving protein, lipid, energy metabolism (e.g., increased glycolysis dependency). change sensitizes anti-proliferative which instead induces opposite changes mitochondrial oxidative phosphorylation). provide evidence inhibits growth, at least part, through suppressor CDKN1C/p57Kip2. Conclusions Collectively, our study reveals microenvironment influences susceptibility provides unprecedented for conditions, vitro Our findings may explain, reason asthmatic patients suggest suitability trials as therapeutic approach fight cancer.

Язык: Английский

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Genome-wide association analysis reveals the genetic basis of thermal tolerance in dwarf surf clam Mulinia lateralis

Genomics, Год журнала: 2024, Номер 116(5), С. 110904 - 110904

Опубликована: Июль 29, 2024

Recently, elevated seawater temperatures have resulted numerous adverse effects, including significant mortality among bivalves. The dwarf surf clam, Mulinia lateralis, is considered a valuable model species for bivalve research due to its rapid growth and short generation time. successful cultivation in laboratory setting throughout entire life cycle makes it an ideal candidate exploring the potential mechanisms underlying responses thermal stress. In this study, total of 600 clams were subjected 17-day stress experiment at temperature 30 °C which semi-lethal species. Ninety individuals who perished initially classified as heat-sensitive populations (HSP), while 89 survived heat-tolerant (HTP). Subsequently, 179 then sequenced, 21,292 single nucleotide polymorphisms (SNPs) genotyped downstream analysis. heritability estimate survival status was found be 0.375 ± 0.127 suggesting genetic basis tolerance trait. Furthermore, genome-wide association study (GWAS) identified three SNPs 10 genes associated with trait M. lateralis. These involved ETHR/EHF signaling pathway played pivotal role signal sensory, cell adhesion, oxidative stress, DNA damage repair, etc. Additionally, qPCR results indicated that, excluding MGAT4A, ZAN, RFC1 genes, all others exhibited significantly higher expression HTP (p < 0.05), underscoring critical involvement lateralis' tolerance. unveil presence standing variations highlighting regulatory bivalve's response contribute comprehension

Язык: Английский

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