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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
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 | GSE111352 | GEO
Project description:S1PR3–G12-biased agonist ALESIA targets cancer metabolism and promotes glucose starvation
| PRJNA601208 | ENA
Project description:S1PR3–G12-biased agonist ALESIA targets cancer metabolism and promotes glucose starvation [HeLa RNA-seq]
| PRJNA601211 | ENA
Project description:S1PR3–G12-biased agonist ALESIA targets cancer metabolism and promotes glucose starvation [MCF-7 RNA-seq]
| PRJNA436703 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-03-29 | GSE246790 | GEO
Project description:Cancer cells often rely on glycolysis to obtain energy and support anabolic growth. Several studies showed that glycolytic cells are susceptible to cell death when subjected to low glucose availability or to lack of glucose. However, some cancer cells, including glycolytic ones, can efficiently acquire higher tolerance to glucose depletion, leading to their survival and aggressiveness. Although increased resistance to glucose starvation has been shown to be a consequence of signaling pathways and compensatory metabolic routes activation, the full repertoire of the underlying molecular alterations remain elusive. Using omics and computational analyses, we found that cyclic adenosine monophosphate-Protein Kinase A (cAMP-PKA) axis activation is fundamental for cancer cell resistance to glucose starvation and anoikis. Notably, here we show that such a PKA-dependent survival is mediated by parallel activation of autophagy and glutamine utilization that in concert concur to attenuate the endoplasmic reticulum (ER) stress and to sustain cell anabolism. Indeed, the inhibition of PKA-mediated autophagy or glutamine metabolism increased the level of cell death, suggesting that the induction of autophagy and metabolic rewiring by PKA is important for cancer cellular survival under glucose starvation. Importantly, both processes actively participate to cancer cell survival mediated by suspension-activated PKA as well. In addition we identify also a PKA/Src mechanism capable to protect cancer cells from anoikis. Our results reveal for the first time the role of the versatile PKA in cancer cells survival under chronic glucose starvation and anoikis and may be a novel potential target for cancer treatment.
| S-EPMC4792400 | biostudies-literature
Project description:CD44 is a single-pass cell surface glycoprotein that is distinguished as the first molecule used to identify cancer stem cells in solid tumors based on its expression. In this regard, the CD44high cell population demonstrates not only the ability to regenerate a heterogeneous tumor, but also the ability to self-regenerate when transplanted into immune-deficient mice. However, the exact role of CD44 in cancer stem cells remains unclear in part because CD44 exists in various isoforms due to alternative splicing. Methods: Gain- and loss-of-function methods in different models were used to investigate the effects of CD44 on breast cancer stemness. Cancer stemness was analyzed by detecting SOX2, OCT4 and NANOG expression, ALDH activity, side population (SP) and sphere formation. Glucose consumption, lactate secretion and reactive oxygen species (ROS) levels were detected to assess glycolysis. Western blot, immunohistochemical staining, ELISA and TCGA dataset analysis were performed to determine the association of CD44ICD and PFKFB4 with clinical cases. A PFKFB4 inhibitor, 5MPN, was used in a xenograft model to inhibit breast cancer development. Results: In this report, we found that the shortest CD44 isoform (CD44s) inhibits breast cancer stemness, whereas the cleaved product of CD44 (CD44ICD) promotes breast cancer stemness. Furthermore, CD44ICD interacts with CREB and binds to the promoter region of PFKFB4, thereby regulating PFKFB4 transcription and expression. The resultant PFKFB4 expression facilitates the glycolysis pathway (vis-à-vis oxidative phosphorylation) and promotes stemness of breast cancer. In addition, we found that CD44ICD and PFKFB4 expressions are generally up-regulated in the tumor portion of breast cancer patient samples. Most importantly, we found that 5MPN (a selective inhibitor of PFKFB4) suppresses CD44ICD-induced tumor development. Conclusion: CD44ICD promotes breast cancer stemness via PFKFB4-mediated glycolysis, and therapies that target PFKFB4 (e.g., 5MPN therapy) may lead to improved outcomes for cancer patients.
| S-EPMC6299690 | biostudies-literature
Project description:A major aspect of microbial metabolic engineering is the development of chassis hosts that have favorable global metabolic phenotypes, and can be further engineered to produce a variety of compounds. In this work, we focus on the problem of decoupling growth and production in the model bacterium Escherichia coli, and in particular on the maintenance of active metabolism during nitrogen-limited stationary phase. We find that by overexpressing the enzyme PtsI, a component of the glucose uptake system that is inhibited by α-ketoglutarate during nitrogen limitation, we are able to achieve a fourfold increase in metabolic rates. Alternative systems were also tested: chimeric PtsI proteins hypothesized to be insensitive to α-ketoglutarate did not improve metabolic rates under the conditions tested, whereas systems based on the galactose permease GalP suffered from energy stress and extreme sensitivity to expression level. Overexpression of PtsI is likely to be a useful arrow in the metabolic engineer's quiver as productivity of engineered pathways becomes limited by central metabolic rates during stationary phase production processes.
| S-EPMC5516864 | biostudies-literature
Project description:Sphingosine-1-phosphate (S1P) regulates numerous important physiological functions, including immune response and vascular integrity, via its cognate receptors (S1PR1 to S1PR5); however, it remains unclear how S1P activates S1PRs upon binding. Here, we determined the crystal structure of the active human S1PR3 in complex with its natural agonist S1P at 3.2-Å resolution. S1P exhibits an unbent conformation in the long tunnel, which penetrates through the receptor obliquely. Compared with the inactive S1PR1 structure, four residues surrounding the alkyl tail of S1P (the "quartet core") exhibit orchestrating rotamer changes that accommodate the moiety, thereby inducing an active conformation. In addition, we reveal that the quartet core determines G protein selectivity of S1PR3. These results offer insight into the structural basis of activation and biased signaling in G protein-coupled receptors and will help the design of biased ligands for optimized therapeutics.
| S-EPMC8189593 | biostudies-literature