Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Cell fusion enhances energy metabolism of mesenchymal tumor hybrid cells to sustain their proliferation and invasion

ABSTRACT: Cell-to-cell fusion is emerging as a key element of the metastatic process in various cancer types. We recently showed that hybrids made from the spontaneous merging of pre-malignant (IMR90 E6E7, i.e. E6E7) and malignant (IMR90 E6E7 RST, i.e. RST) mesenchymal cells recapitulate the main features of human undifferentiated pleomorphic sarcoma (UPS), with a highly rearranged genome and increased spreading capacities. To better characterize the intrinsic properties of these hybrids, we investigated here their metabolic energy profile compared to their parents. Our results unveiled that hybrids harbored a Warburg-like metabolism, like their RST counterparts. However, hybrids displayed a much greater metabolic activity, enhancing glycolysis to proliferate. Interestingly, modifying the metabolic environmental conditions through the use of 5-aminoimidazole-4-carbox-amide-1-β-D-ribofuranoside (AICAR), an activator of the 5’-adenosine monophosphate (AMP)-activated protein kinase (AMPK), specifically reduced the growth of hybrids, and also abrogated the invasive capacity of hybrids displaying enhanced glycolysis. Furthermore, AICAR efficiently blocked the tumoral features related to the aggressiveness of human UPS cell lines. Altogether, our findings strongly suggest that hybrids rely on higher energy flux to proliferate and that a drug altering this metabolic equilibrium could impair their survival and be potentially considered as a novel therapeutic strategy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171471 | GEO | 2021/08/04

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Combinatorial targeting of glycolysis and oxidative phosphorylation suppresses tumor growth and metastases.

Project description:The Warburg effect, consisting of increased glucose uptake and glycolysis, provides metabolic energy as well as cellular building blocks for tumor growth. Inhibition of the Warburg effect with 2-deoxyglucose (2DG) has been explored in clinical trials with limited efficacy. Blockage of glycolysis can induce autopahgy resulting in alternative energy generation through oxidative phosphorylation providing a potential bypass of the effects of inhibition of glycolysis. Here in we demonstrate that activation of AMPK, as a consequence of energetic stress, induces mitochondrial energy production potentially bypassing the effects of glycolysis inhibition. We thus combined blockage of glycolysis by 2DG with inhibition of the electron transfer complex I (ETC1) in the mitochondria with the clinically applicable antidiabetic drug metformin. The combination resulted in activation of AMPK and autopahgy that however rendered eventual depletion of ATP and cell death. Furthermore, combined inhibition of glycolysis and mitochondrial respiration inhibited tumor growth and markedly decreased metastatic capacity in vivo. In order to understand the mechanism of these metabolic inhibitors, we performed whole genome transcriptional analysis. Human SK-4 esophageal cancer cell lines were treated with 5 different treatment groups [2 deoxy glucose (4mM), Metformin (5mM), AICAR (2mM), 2 deoxy glucose (4mM) plus Metformin (5mM) and 2 deoxy glucose (4mM) plus AICAR (2mM)] with non treated control groups for 12 hrs. Each groups was quadruplicated. Microarray experiments and data analysis were done at Dept. of Systems Biology, MDACC (Houston, USA)

2012-12-31 | E-GEOD-16816 | biostudies-arrayexpress

Effect of AICAR monophosphate and AICAr riboside accumulation on global transcription

Project description:AICAR monophosphate (5-Aminoimidazole-4-carboxamide ribonucleotide) is a metabolic intermediate of the de novo purine synthesis pathway presenting highly promising metabolic and antiproliferative properties. Yeast mutants accumulating AICAR are auxotroph for histidine. A screening for suppressors of this phenotype identified recessive and dominant mutants that result in lowering intracellular AICAR concentration. The recessive mutants affect adenosine kinase which is shown here to catalyze the phosphorylation of AICAR riboside in yeast. The dominant mutants strongly enhance the capacity of the alkaline phosphatase Pho13p to dephosphorylate succinyl-AICAR monophosphate into the non-toxic riboside form. By combining these mutants to transcriptomic and metabolomic analyses, we establish that in yeast both toxic and physiological responses to AICAR are linked to the concentration of the monophosphate form, while the nucleoside moiety has no effect even at high concentration. Finally, we establish that (S)AICAR concentration varies under physiological conditions, thus modulating transcriptional regulation of purine pathway genes. This SuperSeries is composed of the SubSeries listed below.

2011-07-11 | GSE29324 | GEO

Targeted inhibition of ubiquitin signaling reverses the metabolic reprogramming and suppresses Glioblastoma growth

Project description:Glioblastoma (GBM) is the most frequent and aggressive form of primary brain tumor in the adult population, and the high recurrence rate and resistance to current therapeutics urgently demand a better therapy for this disease. Regulation of protein stability by the ubiquitin proteasome system (UPS) represents an important control mechanism of cell growth. Deregulation of UPS is mechanistically linked to the development and progression of a variety of human cancers, including GBM. Thus, UPS system represents a valuable target for GBM treatment. Here, we find that the E3 ligase praja2 selectively marks primary IDH1-wild type GBM. By using an integrated approach, including proteomics, transcriptomics and metabolic profiling, we identify praja2 as a main component of a signaling network that regulates cancer cell growth and metabolism. We show that praja2 binds and regulates the stability of the Kinase Suppressor of Ras 2 (KSR2) and as consequence, the activity of the downstream AMP-dependent protein kinase (AMPK) in GBM cells. By degrading KSR2, praja2 attenuates the oxidative metabolism and promotes the aerobic glycolysis (Warburg effect). Brain delivery of siRNAs targeting praja2 upregulates KSR2 and negatively impacted on GBM growth, reducing the tumor size and significantly improving the survival rate of treated mice. These data highlight the role of praja2 as an essential regulator of cancer cell metabolism, and as a preferential therapeutic target to suppress GBM growth

2022-06-29 | E-MTAB-11137 | biostudies-arrayexpress

Metabolomics Workbench ST000339 - GNPS - Metabolites in peritoneal macrophages and bone marrow derived macrophages

Project description:"Experiment looks to identify metabolites in the major metabolic pathways, i.e. glycolysis, tca, urea cycle and ppp along with amino acids."

2018-08-02 | MSV000082689 | GNPS

Effect of AICAR and SAICAR accumulation on global transcription (first part)

Project description:We investigated the effects of AICAR and SAICAR accumulation on transcriptional regulation of purine biosynthesis and other metabolic pathways. In this work, global transcription analyses were combined to measurements of intracellular nucleotides pools by HPLC. Keywords: Comparative genomic transcription analysis on total RNA from cells accumulating or not AICAR and SAICAR nucleotide derivatives.

2009-05-15 | GSE13182 | GEO

Effect of AICAR and SAICAR accumulation on global transcription (second part)

Project description:We investigated the effects of AICAR and SAICAR accumulation on transcriptional regulation of purine biosynthesis and other metabolic pathways. These data were compared to those obtained in the ade16ade17 vs WT data set to determine the transcriptional effects associated to AICAR/SAICAR accumulation and those due to ade16 and ade17 deletions. In this work, global transcription analyses were combined to measurements of intracellular nucleotides pools by HPLC Keywords: Comparative genomic transcription analysis on total RNA from cells accumulating or lacking AICAR and SAICAR nucleotide derivatives.

2009-05-15 | GSE13183 | GEO

Sweet corn: low- vs. high-yielding hybrids

Project description:Transcriptional profiling of sweet corn plant density (crowding stress) tolerance influencing yield. Tolerance to crowding stress has played a crucial role in improving agronomic productivity in field corn; however, commercial sweet corn hybrids vary greatly in crowding stress tolerance. The experiment was conducted to 1) explore transcriptional changes among sweet corn hybrids with differential yield under crowding stress, 2) identify relationships between phenotypic responses and gene expression patterns, and 3) identify groups of genes associated with yield and crowding stress tolerance. Under conditions of crowding stress, three high-yielding and three low-yielding sweet corn hybrids were grouped for transcriptional and phenotypic analyses. Transcriptional analyses identified from 372 to 859 common differentially expressed genes (DEGs) for each hybrid. Large gene expression pattern variation among hybrids and only 26 common DEGs across all hybrid comparisons were identified, suggesting each hybrid has a unique response to crowding stress. Over-represented biological functions of DEGs also differed among hybrids. Strong correlation was observed between: 1) modules with up-regulation in high-yielding hybrids and yield traits, and 2) modules with up-regulation in low-yielding hybrids and plant/ear traits. Modules linked with yield traits may be important crowding stress response mechanisms influencing crop yield. Functional analysis of the modules and common DEGs identified candidate crowding stress tolerant processes in photosynthesis, glycolysis, cell wall, carbohydrate/nitrogen metabolic process, chromatin, and transcription regulation. Moreover, these biological functions were greatly inter-connected, indicating the importance of improving the mechanisms as a network. 3 high-and 3 low-yielding hybrids with 2-3 biological replications grown under high population density (crowding stress)

2016-01-05 | E-GEOD-73435 | biostudies-arrayexpress

Mutant telomerase RNAs induce DNA damage and apoptosis via the TRF2-ATM pathway in telomerase-overexpressing primary fibroblasts

Project description:Mutant template human telomerase RNAs (MT-hTers) have been shown to induce apoptosis in various cancer cells with high telomerase activity. However, the mechanism by which MT-hTers inhibit growth of cancer cells and their effects on normal cells remain unknown. To determine the effects of MT-hTers on normal cells, MT-hTer-47A and -AU5 were introduced into IMR90 lung fibroblasts that have low telomerase levels. Growth of IMR90 cells following MT-hTers infection was not significantly impaired; however, similar treatments in telomerase-overexpressing IMR90 (IMR90 WThTERT) cells inhibited cell proliferation and induced apoptosis. Confocal microscopy showed that MT-hTers induced DNA damage foci i.e. 53BP1 and γ-H2AX in IMR90 WThTERT cells. Microarray analysis revealed that GADD45γ was significantly elevated in MT-hTers treated IMR90 WThTERT cells. MT-hTers also induced ATM phosphorylation at Ser 1981 in IMR90 WThTERT cells, and Western blot analysis revealed high levels of phosphorylated p53 following down-regulation of cellular TRF2 expression in MT-hTers treated IMR90 WThTERT cells. Taken together, we have elucidated that MT-hTers induce double-stranded DNA breaks (DSBs)-like damages in telomerase-positive IMR90 WThTERT cells following phosphorylation of ATM and p53 via suppression of TRF2 which eventually may have led to apoptosis via elevation of GADD45γ.

2011-05-29 | GSE24975 | GEO

Hybrids assimilate organ-specific metastasis gene signatures from both parental cells

Project description:Spontaneous cell fusion of MDA-MB-231 bone-metastatic subline Bm (i.e., SCP2) and lung metastatic subline Lm (i.e., LM2) gave rise to hybrid lines BLm-FACS or BLm-DRUG, as well as its single clones (#8, #12, #18). The hybrids acquired the metastasis tropisms from both parental cells. Expression profiles of the parental cells, the hybrids and several previously characterized MDA-MB-231 metastatic derivatives were compared. Hierarchical clustering showed the hybrids assimilated the organ-specific metastasis gene signatures from both parental cells. Keywords: Cell type comparison

2009-05-06 | GSE14244 | GEO

Sweet corn: low- vs. high-yielding hybrids

2016-01-05 | GSE73435 | GEO