The glycerol backbone of phospholipids derives from noncarbohydrate precursors in starved lung cancer cells

Leithner, Katharina; Triebl, Alexander; Trötzmüller, Martin; Hinteregger, Barbara; Leko, Petra; Wieser, Beatrix I.; Grasmann, Gabriele; Bertsch, Alexandra; Züllig, Thomas; Stacher, Elvira; Valli, Alessandro; Ruth, Peter; Olschewski, Andrea; Harris, Adrian L.; Köfeler, Harald; Olschewski, Horst; Hrzenjak, Andelko

doi:10.1073/pnas.1719871115

Cited by 52 publications

(65 citation statements)

References 50 publications

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“…Cellular PEP levels are also maintained by the PEPCK-dependent cataplerosis of TCA cycle carbons that contribute to the synthesis of glycolytic intermediates (Hyrossova et al, unpublished), serine/glycine [19] and triglycerides [20,21]. In most tumor models, and specifically in the cellular models utilized in this work, the mitochondrial isoform of PEPCK (PEPCK-M) plays this key role as it is the only isoform of PEPCK expressed [22].…”

Section: Glycolytic and Cataplerotic Fluxes Towards Pep Cooperate To mentioning

confidence: 99%

Phosphoenolpyruvate from Glycolysis and PEPCK Regulate Cancer Cell Fate by Altering Cytosolic Ca2+

Moreno-Felici

Hyroššová

Aragó

et al. 2019

Cells

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Changes in phosphoenolpyruvate (PEP) concentrations secondary to variations in glucose availability can regulate calcium signaling in T cells as this metabolite potently inhibits the sarcoplasmic reticulum Ca 2+ /ATPase pump (SERCA). This regulation is critical to assert immune activation in the tumor as T cells and cancer cells compete for available nutrients. We examined here whether cytosolic calcium and the activation of downstream effector pathways important for tumor biology are influenced by the presence of glucose and/or cataplerosis through the phosphoenolpyruvate carboxykinase (PEPCK) pathway, as both are hypothesized to feed the PEP pool. Our data demonstrate that cellular PEP parallels extracellular glucose in two human colon carcinoma cell lines, HCT-116 and SW480. PEP correlated with cytosolic calcium and NFAT activity, together with transcriptional up-regulation of canonical targets PTGS2 and IL6 that was fully prevented by CsA pre-treatment. Similarly, loading the metabolite directly into the cell increased cytosolic calcium and NFAT activity. PEP-stirred cytosolic calcium was also responsible for the calmodulin (CaM) dependent phosphorylation of c-Myc at Ser62, resulting in increased activity, probably through enhanced stabilization of the protein. Protein expression of several c-Myc targets also correlated with PEP levels. Finally, the participation of PEPCK in this axis was interrogated as it should directly contribute to PEP through cataplerosis from TCA cycle intermediates, especially in glucose starvation conditions. Inhibition of PEPCK activity showed the expected regulation of PEP and calcium levels and consequential downstream modulation of NFAT and c-Myc activities. Collectively, these results suggest that glucose and PEPCK can regulate NFAT and c-Myc activities through their influence on the PEP/Ca 2+ axis, advancing a role for PEP as a second messenger communicating metabolism, calcium cell signaling, and tumor biology.

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Section: Glycolytic and Cataplerotic Fluxes Towards Pep Cooperate To mentioning

confidence: 99%

Phosphoenolpyruvate from Glycolysis and PEPCK Regulate Cancer Cell Fate by Altering Cytosolic Ca2+

Moreno-Felici

Hyroššová

Aragó

et al. 2019

Cells

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“…For the glycerophospholipid metabolism term, phosphoenolpyruvate carboxykinase (PEPCK) has been shown to promote cancer cell survival under conditions of nutrient deprivation, a typical feature in solid cancers, as well as cancer growth (Méndez-Lucas et al, 2014;Leithner et al, 2015;Montal et al, 2015;Vincent et al, 2015). Recently, Leithner et al (2018) further showed that mitochondrial PEPCK (PEPCK-M) mediates the synthesis of glycerol phosphate from noncarbohydrate precursors, and that PEPCKM is needed to maintain the levels of glycerophospholipids, major constituents of biomembranes, in starved lung cancer cells.…”

Section: Enrichment Analysis Of Pathways and Biological Processesmentioning

confidence: 99%

A Novel Method to Efficiently Highlight Nonlinearly Expressed Genes

et al. 2020

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For precision medicine, there is a need to identify genes that accurately distinguish the physiological state or response to a particular therapy, but this can be challenging. Many methods of analyzing differential expression have been established and applied to this problem, such as t-test, edgeR, and DEseq2. A common feature of these methods is their focus on a linear relationship (differential expression) between gene expression and phenotype. However, they may overlook nonlinear relationships due to various factors, such as the degree of disease progression, sex, age, ethnicity, and environmental factors. Maximal information coefficient (MIC) was proposed to capture a wide range of associations of two variables in both linear and nonlinear relationships. However, with MIC it is difficult to highlight genes with nonlinear expression patterns as the genes giving the most strongly supported hits are linearly expressed, especially for noisy data. It is thus important to also efficiently identify nonlinearly expressed genes in order to unravel the molecular basis of disease and to reveal new therapeutic targets. We propose a novel nonlinearity measure called normalized differential correlation (NDC) to efficiently highlight nonlinearly expressed genes in transcriptome datasets. Validation using six real-world cancer datasets revealed that the NDC method could highlight nonlinearly expressed genes that could not be highlighted by t-test, MIC, edgeR, and DEseq2, although MIC could capture nonlinear correlations. The classification accuracy indicated that analysis of these genes could adequately distinguish cancer and paracarcinoma tissue samples. Furthermore, the results of biological interpretation of the identified genes suggested that some of them were involved in key functional pathways associated with cancer progression and metastasis. All of this evidence suggests that these nonlinearly expressed genes may play a central role in regulating cancer progression.

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“…Partially, this occurs by circumventing the glycolytic pathway and instead using some steps of gluconeogenesis from noncarbohydrate precursors to overcome metabolic stress (for review, see [8]). The key enzyme mediating gluconeogenesis, phosphoenolpyruvate carboxykinase (PEPCK), has been recently discovered to replenish glycolytic pools in cancer cells of different origins and thus to mediate abbreviated gluconeogenesis [9][10][11][12][13]. In numerous studies, PEPCK was shown to enhance tumor cell metabolic flexibility under glucose deprivation [8].…”

Section: Introductionmentioning

confidence: 99%

“…There are two isoforms of PEPCK: the cytoplasmic isoform PCK1, and PCK2, the mitochondrial isoform [16,17]. In tumor cells of various origins, PCK1 or PCK2 have been found to mediate abbreviated gluconeogenesis, especially under conditions of glucose deprivation, thus contributing to anabolic metabolism [9,[11][12][13]. The downstream metabolic pathways fueled by PCK1 or PCK2 in cancer cells include the biosynthesis of the phospholipid glycerol backbone [13], serine [11], or ribose [12,18].…”

Section: Introductionmentioning

confidence: 99%

Distribution and prognostic significance of gluconeogenesis and glycolysis in lung cancer

et al. 2020

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The glycerol backbone of phospholipids derives from noncarbohydrate precursors in starved lung cancer cells

Cited by 52 publications

References 50 publications

Phosphoenolpyruvate from Glycolysis and PEPCK Regulate Cancer Cell Fate by Altering Cytosolic Ca2+

Phosphoenolpyruvate from Glycolysis and PEPCK Regulate Cancer Cell Fate by Altering Cytosolic Ca2+

A Novel Method to Efficiently Highlight Nonlinearly Expressed Genes

Distribution and prognostic significance of gluconeogenesis and glycolysis in lung cancer

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