NMR metabolomics highlights sphingosine kinase‐1 as a new molecular switch in the orchestration of aberrant metabolic phenotype in cancer cells

Bernacchioni, Caterina; Ghini, Veronica; Cencetti, Francesca; Japtok, Lukasz; Donati, Chiara; Bruni, Paola; Turano, Paola

doi:10.1002/1878-0261.12048

Cited by 37 publications

(34 citation statements)

References 62 publications

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“…Analogously, the metabolomic profiles highlighted an increase in the levels of the TCA cycle intermediates succinate and fumarate (Fig 3A), which accumulate due to inefficient TCA metabolism (Bernacchioni et al, 2017;Caracausi et al, 2018).…”

Section: Figure 2 Metabolomic and Proteomic Profiles Of Different Comentioning

confidence: 82%

Integrated metabolomics and proteomics of symptomatic and early pre-symptomatic states of colitis

Shimshoni

Ghini

Solomonov

et al. 2020

Preprint

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Two murine models for colitis were used to study multi-level changes and derive molecular signatures of colitis onset and development. By combining metabolomics data on tissues and fecal extracts with proteomics data on tissues, we provide a comprehensive picture of the metabolic profile of acute and chronic states of the disease, and most importantly, of two early pre-symptomatic states. We show that, increased anaerobic glycolysis, accompanied by altered TCA cycle and oxidative phosphorylation, associates with inflammation-induced hypoxia taking place in colon tissues. We also demonstrate significant changes in the metabolomic profiles of fecal extracts in different colitis states, most likely associated with the dysbiosis characteristic of colitis, as well as the dysregulated tissue metabolism. Most remarkably, strong and distinctive tissue and fecal metabolomic signatures can be detected before onset of symptoms. These results highlight the diagnostic potential of global metabolomics for inflammatory diseases.

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Section: Figure 2 Metabolomic and Proteomic Profiles Of Different Comentioning

confidence: 82%

Integrated metabolomics and proteomics of symptomatic and early pre-symptomatic states of colitis

Shimshoni

Ghini

Solomonov

et al. 2020

Preprint

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“…We show that LDHA expression under normoxic conditions potentiates extracellular acidification (ECAR) with increased lactate production and LDH enzyme activity, but oxygen consumption rate does not change, suggesting that LDHA promotes glycolysis in tumor cells even with an adequate oxygen supply (Bernacchioni et al ., 2017). This indicates that high rates of glycolysis in many tumors are required and necessary for tumor growth and are not just compensation for mitochondrial dysfunction (Bui and Thompson, 2006; Fantin et al ., 2006).…”

Section: Discussionmentioning

confidence: 99%

PGC1β regulates multiple myeloma tumor growth through LDHA‐mediated glycolytic metabolism

Zhang

Chen

et al. 2018

Molecular Oncology

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Multiple myeloma (MM) is an incurable hematologic malignancy due to inevitable relapse and chemoresistance development. Our preliminary data show that MM cells express high levels of PGC1β and LDHA. In this study, we investigated the mechanism behind PGC1β‐mediated LDHA expression and its contribution to tumorigenesis, to aid in the development of novel therapeutic approaches for MM. Real‐time PCR and western blotting were first used to evaluate gene expression of PGC1β and LDHA in different MM cells, and then, luciferase reporter assay, chromatin immunoprecipitation, LDHA deletion report vectors, and siRNA techniques were used to investigate the mechanism underlying PGC1β‐induced LDHA expression. Furthermore, knockdown cell lines and lines stably overexpressing PGC1β or LDHA lentivirus were established to evaluate in vitro glycolysis metabolism, mitochondrial function, reactive oxygen species (ROS) formation, and cell proliferation. In addition, in vivo xenograft tumor development studies were performed to investigate the effect of PGC1β or LDHA expression on tumor growth and mouse survival. We found that PGC1β and LDHA are highly expressed in different MM cells and LDHA is upregulated by PGC1β through the PGC1β/RXRβ axis acting on the LDHA promoter. Overexpression of PGC1β or LDHA significantly potentiated glycolysis metabolism with increased cell proliferation and tumor growth. On the other hand, knockdown of PGC1β or LDHA largely suppressed glycolysis metabolism with increased ROS formation and apoptosis rate, in addition to suppressing tumor growth and enhancing mouse survival. This is the first time the mechanism underlying PGC1β‐mediated LDHA expression in multiple myeloma has been identified. We conclude that PGC1β regulates multiple myeloma tumor growth through LDHA‐mediated glycolytic metabolism. Targeting the PGC1β/LDHA pathway may be a novel therapeutic strategy for multiple myeloma treatment.

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“…Samples were prepared in 5.00 mm NMR tubes by mixing 60 μL of a potassium phosphate buffer (1.5 M K2HPO4, 100% (v/v) 2 H2O, 10 mM sodium trimethylsilyl [2,2,3,3− 2 H4]propionate (TMSP), pH 7.4) and 540 μL of sample. Spectral acquisition and processing were performed according to procedures developed at CERM [47][48][49][50][51][52] . All the spectra were recorded using a Bruker 600 MHz spectrometer (Bruker BioSpin) operating at 600.13 MHz proton Larmor frequency and equipped with a 5 mm PATXI 1 H-13 C-15 N and 2 H-decoupling probe including a z axis gradient coil, an automatic tuning-matching (ATM) and an automatic and refrigerate sample changer (SampleJet).…”

Section: Modellingmentioning

confidence: 99%

Diauxie and co-utilization are not exclusive during growth in nutritionally complex environments

Perrin

Giovannini

et al. 2019

Preprint

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The classic view of microbial growth strategy when multiple carbon sources are available states that they either metabolize them sequentially (diauxic growth) or simultaneously (coutilization). This perspective is biased by the fact that this process has been mainly analysed in over-simplified laboratory settings, i.e. using a few model microorganisms and growth media containing only two alternative compounds. Models concerning the mechanisms and the dynamics regulating nutrients assimilation strategies in conditions that are closer to the ones found in natural settings (i.e. with many alternative carbon/energy sources) are missing. Here, we show that bacterial co-utilization and sequential uptake of multiple substrates can coexist when multiple possible nutrients are provided in the same growth experiment, leading to an efficient exploitation of nutritionally complex settings. The order of nutrient uptake is determined by the actual biomass yield (and growth rate) that can be achieved when the same compounds are provided as single carbon sources. Finally, using two alternative theoretical models we show that this complex metabolic phenotype can be explained by a tight regulation process that allows microbes to actively modulate the different assimilatory pathways involved.

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NMR metabolomics highlights sphingosine kinase‐1 as a new molecular switch in the orchestration of aberrant metabolic phenotype in cancer cells

Cited by 37 publications

References 62 publications

Integrated metabolomics and proteomics of symptomatic and early pre-symptomatic states of colitis

Integrated metabolomics and proteomics of symptomatic and early pre-symptomatic states of colitis

PGC1β regulates multiple myeloma tumor growth through LDHA‐mediated glycolytic metabolism

Diauxie and co-utilization are not exclusive during growth in nutritionally complex environments

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