Project description:Anti-estrogens have had a limited impact on breast cancer (BC) prevention. Novel agents with better tolerability, and efficacy beyond estrogen receptor (ER) positive BC are needed. We studied licochalcone A (LicA) for ER-agnostic BC prevention. We demonstrated that LicA significantly reduced proliferation in seven human breast cell lines and suppressed ER+ and ER- xenograft tumors in mice. We confirmed these observations ex vivo in contralateral unaffected breast (CUB) of women with unilateral sporadic BC, and breast cancer cell lines using RNA sequencing, metabolism flux modeling, confirmatory NanoString metabolic pathway panel analysis in independent sets of specimens, proteomics, and western blots. We found that LicA targets sterol regulatory element binding protein 1 (SREBP1) with subsequent metabolic-inflammatory changes, lowering spatiotemporally resolved cholesterol levels inside malignant cells to the levels in normal mammary cells. Mechanistically, in CUBs we observed that LicA downregulated PI3K-AKT-SREBP1-dependent lipogenesis, NF-kB-dependent inflammation, and de novo nucleotide biosynthesis, stalling proliferation. Studies in cell lines showed suppression of PI3K and AKT phosphorylation, SREBP1 protein expression, and the SREBP1-dependent enzymes such as ACAT2, ACLY, FASN, SCD, consistent with reduced NEDD8 required for SREBP1 stabilization. We found significant reduction in NF-kB expression, its nuclear translocation mediator karyopherin β1, and prostaglandin E2 synthesis. We demonstrated a reduction in PRPS1-catalyzed de novo nucleotide biosynthesis, and downregulation of proliferative markers MKI67, RRM2, and the survival marker BCL2. LicA reduces pro-tumorigenic aberrations in lipid homeostasis and inflammation through SREBP1. It is a promising non-endocrine candidate for BC prevention. Future studies in immunocompetent BC prevention models are warranted.

2025-09-24 | GSE290030 | GEO

Endogenously produced cyanide supports bioenergetics and exerts cytoprotective effects in mammals_Mice-liver

Project description:Small, gaseous molecules, known as gasotransmitters (NO, CO, H2S), are produced endogenously in mammalian cells and serve important biological roles. Cyanide (CN) is 35 known as an endogenous mediator in plants and bacteria, while in mammals it has been mainly viewed as a toxin. Here we show that low concentrations of CN are endogenously generated in mouse liver and human hepatocytes from glycine and HOCl-in lysosomes. CN diffuses out of the lysosome to reach various cellular compartments and is detectable in circulating blood. Endogenous CN–via protein cysteine cyanylation and removal of glutathione from proteins 40–exerts pluripotent effects on cell metabolism and gene expression. Endogenous CN production supports cellular ATP production, in part, via increased free fatty acid oxidation. CN also supports cell proliferation and exerts cytoprotective effects. Controlled CN donation exerts cytoprotective effects in vitro and in vivo models of hypoxia and reoxygenation. In this part of the study, we used liver samples from WT mice that were either treated with glycine or left untreated. Glycine is known to produce cyanide as a by-product of metabolism. Our objective was to identify the first the targets of cysteine cyanilation. As no enrichment method is available for this modification, we employed direct detection of cyanilated cysteines peptides in the proteome.

2025-05-06 | PXD046065 | Pride

Reprogramming SREBP1-dependent lipogenesis and inflammation in high-risk breast with licochalcone A: a novel path to cancer prevention

Project description:This study investigates the effects of Licochalcone A (LicA) on protein stability in breast cancer cells using Proteome Integral Solubility Alterations (PISA) proteomics. We treated MCF-7 (ER+) and MDA-MB-231 (ER-) cells with LicA (10 µM) for 24 hours and subjected them to temperature-dependent protein solubility profiling. Thermal denaturation assays (40-65°C) followed by LC-MS/MS analysis with TMT labeling were performed to identify differentially stabilized and destabilized proteins. Our results indicate that LicA significantly destabilizes proteins involved in SREBP1-dependent lipogenesis, PI3K-AKT signaling, and NF-kB-mediated inflammation, while stabilizing pathways associated with antioxidant defense and metabolic reprogramming. These findings suggest a mechanism by which LicA alters the breast cancer proteome, leading to reduced tumor proliferation.

2025-09-29 | PXD061086 | Pride

Intraindividual rDNA copy number variation and methylation in humans

Project description:The absolute number of rDNA transcription units can vary by about one power of ten among individuals. Apart from extensive rDNA copy number (CN) variation and instability in many cancers, there is little information on the extent of intraindividual CN variation between normal s. Here we used droplet digital PCR and deep bisulfite sequencing to determine both the absolute rDNA CN and the number of presumably active CN with a hypomethylated (0-10%) promoter region in up to six different s of 13 autopsy probands. In general, the absolute rDNA CN as well as the frequency of the minor A variant were highly similar between s (cerebellum, cerebrum, colon, heart, intestine, kidney, and liver liver and spleen) of the same individual. However, in some probands absolute CN in one or multiple s was much higher than in the other s., consistent with relaxation/breakdown of the CN control system. The amplified copies were inactivated by promoter methylation and, thus, the number of active CN was largely independent from absolute CN. Collectively, our data suggest that with some notable exceptions absolute and even more active rDNA CN are maintained during development and differentiation in different s of the same individual. Despite the low intraindividual variation active CN appeared to systematically vary between s. Cerebellum, which is characterized by the highest density of non-dividing neuronal cells in the body, consistently exhibited lower active CN than other s. We estimate that a minimum number of > 50 active rDNA TU is required for normal /organ function.

2025-06-16 | GSE297209 | GEO

ena-DATASET-BGI-20-07-2017-06:55:58:975-246 - samples

Project description:There are 5WGS and 35WES sample pairs from the first affiliated hospital of kunming medical university, which belongs to ICGC projects COCA-CN.

| EGAD00001003456 | EGA

Microbacterium sp. 20-116 isolate:cucumber

Project description:Microbacterium sp. 20-116 isolate:cucumber Genome sequencing

| PRJNA1142178 | ENA