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S1PR3–G12-biased agonist ALESIA targets cancer metabolism and promotes glucose starvation [MCF-7 RNA-seq]

ABSTRACT: Cancer tissues possess less glucose than surrounding normal tissue, because cancer cells predominantly produce energy by glycolysis than oxidative phosphorylation even in the presence of an adequate oxygen supply (Warburg effect). We found a novel compound ALESIA which causes apoptosis of malignant cells at a low glucose condition from an original phenotypic screening. Identified target molecule of ALESIA was Sphingosine-1-phosphate receptor 3 (S1PR3). Being different from the natural ligand, ALESIA selectively stimulated S1PR3-G12 coupling to S1PR3 without suppression by β-arrestin recruitment and continuously promoted NO synthesis. To reduce the enhanced oxidative stress, NAPDH production through pentose-phosphate pathway and resulting consumption of glucose were promoted in ALESIA-treated cells. ALESIA therefore accelerated glucose starvation of cancer cells and preferentially killed them both in vitro and in vivo.

ORGANISM(S): Homo sapiens

PROVIDER: GSE111352 | GEO | 2021/02/08

REPOSITORIES: GEO

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S1PR3–G12-biased agonist ALESIA targets cancer metabolism and promotes glucose starvation [HeLa RNA-seq]

Project description:Cancer tissues possess less glucose than surrounding normal tissue, because cancer cells predominantly produce energy by glycolysis than oxidative phosphorylation even in the presence of an adequate oxygen supply (Warburg effect). We found a novel compound ALESIA which causes apoptosis of malignant cells at a low glucose condition from an original phenotypic screening. Identified target molecule of ALESIA was Sphingosine-1-phosphate receptor 3 (S1PR3). Being different from the natural ligand, ALESIA selectively stimulated S1PR3-G12 coupling to S1PR3 without suppression by β-arrestin recruitment and continuously promoted NO synthesis. To reduce the enhanced oxidative stress, NAPDH production through pentose-phosphate pathway and resulting consumption of glucose were promoted in ALESIA-treated cells. ALESIA therefore accelerated glucose starvation of cancer cells and preferentially killed them both in vitro and in vivo.

2021-02-08 | GSE143668 | GEO

S1PR3–G12-biased agonist ALESIA targets cancer metabolism and promotes glucose starvation

Project description:S1PR3–G12-biased agonist ALESIA targets cancer metabolism and promotes glucose starvation

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S1PR3–G12-biased agonist ALESIA targets cancer metabolism and promotes glucose starvation [HeLa RNA-seq]

Project description:S1PR3–G12-biased agonist ALESIA targets cancer metabolism and promotes glucose starvation [HeLa RNA-seq]

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Starvation and chemotherapy

Project description:Tumor chemoresistance is often associated to high aerobic glycolysis rates and reduced oxidative phosphorylation by cancer cells, a phenomenon called the “Warburg effect”. Thus, a treatment reversing the Warburg effect could decrease tumor cell survival both in the presence or absence of chemotherapy. Short-term starvation (STS) could accomplish this task since it is accompanied by a glucose and amino acid decrease and fatty acid increase, which require respiration for energy production. We tested the cytotoxicity of STS+Oxaliplatin on colon cancer cells by Trypan Blue, Carboxyfluorescein Succinimidyl ester and Annexin V staining. Reactive oxygen species production was measured by 2',7'-dichlorodihydrofluorescein diacetate staining. In vitro glucose consumption was evaluated by 18F-Fluoro-deoxyglucose uptake. Gene expression was tested by microarray analysis. Protein expression and activity were studied by western blot, proteomic analyses and spectrophotometric assays. CT26 bearing mice consumed only water for 48 hours (STS) before oxaliplatin treatment. Dynamic micro-Positron Emission Tomography and tumor growth measurements were performed. STS+Oxaliplatin cause a potent suppression of colon carcinoma growth and glucose consumption in in vitro and in vivo models. In CT26 cells, STS down-regulates aerobic glycolysis, and glutaminolysis, while increasing oxidative phosphorylation. STS-dependent increase in O2 consumption is associated with reduced ATP synthesis and increased oxidation. In combination with chemotherapy, these effects of STS cause additive toxicity to cancer cells. Our findings indicate that during and following STS the decreased glucose levels promote an anti-Warburg effect characterized by increased oxygen consumption but failure to generate ATP, resulting in oxidative damage and apoptosis. The experiment comprised for conditions: Control, Starvation, Oxaliplatin, and Starvation plus Oxaliplatin

2015-08-11 | E-GEOD-60653 | biostudies-arrayexpress

S1PR3–G12-biased agonist ALESIA targets cancer metabolism and promotes glucose starvation [MCF-7 RNA-seq]

Project description:S1PR3–G12-biased agonist ALESIA targets cancer metabolism and promotes glucose starvation [MCF-7 RNA-seq]

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Starvation and chemotherapy

2015-08-11 | GSE60653 | GEO

Altered gene expression in the neocortices and hippocampi of the adult S1P2-deficient and S1P3-deficient mice

Project description:Altered gene expression in the sphingosine 1-phosphate receptor 2 (S1P2)-deficient or sphingosine 1-phosphate receptor 3 (S1P3)-deficient brain. Keywords: genetic modification

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Sphingosine kinase 2 in stromal fibroblasts creates a hospitable tumor microenvironment in breast cancer

Project description:Reciprocal interactions between breast cancer cells and the tumor microenvironment are important for cancer progression and metastasis. We report here that the deletion or inhibition of sphingosine kinase 2 (SphK2), which produces sphingosine-1-phosphate (S1P), markedly suppresses syngeneic breast tumor growth and lung metastasis in mice by creating a hostile microenvironment for tumor growth and invasion. SphK2 deficiency decreased S1P and concomitantly increased ceramides, including C16-ceramide, in stromal fibroblasts. Ceramide accumulation suppressed activation of cancer-associated fibroblasts (CAFs) by upregulating stromal p53, which restrained production of tumor-promoting factors to reprogram the tumor microenvironment and restrict breast cancer establishment. Ablation of p53 in SphK2-deficient fibroblasts reversed these effects, enabled CAF activation and promoted tumor growth and invasion. These data uncovered a novel role of SphK2 in regulating non-cell autonomous functions of p53 in stromal fibroblasts and their transition to tumor-promoting CAFs, paving the way for the development of a strategy to target the tumor microenvironment and enhance therapeutic efficacy.

2020-01-01 | GSE136655 | GEO

The phosphorylated prodrug FTY720 is a histone deacetylase Q15 inhibitor that reactivates ERα expression and enhances hormonal therapy for breast cancer

Project description:Nuclear FTY720-P is a potent inhibitor of class I histone deacetylases (HDACs) that enhances histone acetylations and regulates expression of a restricted set of genes independently of its known effects on canonical signaling through sphingosine-1-phosphate (S1P) receptors. We found that FTY720 is phosphorylated in Era-negative breast cancer cells by nuclear sphingosine kinase 2 and accumulates these cells.

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SPHINGOSINE 1-PHOSPHATE MEDIATES ADIPONECTIN RECEPTOR SIGNALING ESSENTIAL FOR LIPID HOMEOSTASIS AND EMBRYOGENESIS

Project description:Cells and organisms require proper membrane composition to function and develop. Phospholipids are the major component of membranes and are primarily acquired through the diet. Given great variability in diet composition, cells must be able to deploy mechanisms that correct deviations from optimal membrane composition and properties. Here, using unbiased lipidomics and proteomics, we found that the embryonic lethality in mice lacking the fluidity regulators Adiponectin Receptors 1 and 2 (AdipoR1/2) is associated with aberrant high saturation of the membrane phospholipids. Using mouse embryonic fibroblasts (MEFs) derived from AdipoR1/2-KO embryos, human cell lines and the model organism C. elegans we found that, mechanistically, AdipoR1/2-derived sphingosine 1-phosphate (S1P) signals in parallel through S1PR3-SREBP1 and PPARγ to sustain the expression of the fatty acid desaturase SCD and maintain membrane properties. Thus, our work identifies an evolutionary conserved pathway by which cells and organism maintain membrane homeostasis and adapt to a variable environment.

2022-12-13 | PXD029163 | Pride

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