PEPCK Coordinates the Regulation of Central Carbon Metabolism to Promote Cancer Cell Growth

Montal, Emily; Dewi, Ruby E.; Bhalla, Kavita; Ou, Lihui; Hwang, Bor Jang; Ropell, Ashley E.; Gordon, Chris; Liu, Wan Ju; DeBerardinis, Ralph J.; Sudderth, Jessica; Twaddel, William; Boros, László G.; Shroyer, Kenneth R.; Duraisamy, Sekhar; Drapkin, Ronny; Powers, Scott; Rohde, Jason M.; Boxer, Matthew B.; Wong, Kwok-Kin; Girnun, Geoffrey D.

doi:10.1016/j.molcel.2015.09.025

Cited by 195 publications

(258 citation statements)

References 33 publications

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“…7F). These data are consistent with recent reports that glucose deprivation results in an increase in Pck expression (33, 34) which promotes metabolic flexibility when nutrients are limiting (35,36). Also, these data show the utility of assessing a phenotype across a series of genetic perturbations.…”

Section: Mpc Deficiency Promotes Metabolic Plasticity In Uterosupporting

confidence: 91%

Requirement for the Mitochondrial Pyruvate Carrier in Mammalian Development Revealed by a Hypomorphic Allelic Series

Bowman

Zhao

Hartung

et al. 2016

Molecular and Cellular Biology

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bGlucose and oxygen are two of the most important molecules transferred from mother to fetus during eutherian pregnancy, and the metabolic fates of these nutrients converge at the transport and metabolism of pyruvate in mitochondria. Pyruvate enters the mitochondrial matrix through the mitochondrial pyruvate carrier (MPC), a complex in the inner mitochondrial membrane that consists of two essential components, MPC1 and MPC2. Here, we define the requirement for mitochondrial pyruvate metabolism during development with a progressive allelic series of Mpc1 deficiency in mouse. Mpc1 deletion was homozygous lethal in midgestation, but Mpc1 hypomorphs and tissue-specific deletion of Mpc1 presented as early perinatal lethality. The allelic series demonstrated that graded suppression of MPC resulted in dose-dependent metabolic and transcriptional changes. Steady-state metabolomics analysis of brain and liver from Mpc1 hypomorphic embryos identified compensatory changes in amino acid and lipid metabolism. Flux assays in Mpc1-deficient embryonic fibroblasts also reflected these changes, including a dramatic increase in mitochondrial alanine utilization. The mitochondrial alanine transaminase GPT2 was found to be necessary and sufficient for increased alanine flux upon MPC inhibition. These data show that impaired mitochondrial pyruvate transport results in biosynthetic deficiencies that can be mitigated in part by alternative anaplerotic substrates in utero. E mbryonic development in eutherian mammals is defined by ongoing metabolic interactions between mother and fetus. Placentas have evolved a sophisticated suite of adaptations to ensure adequate nutrient, gas, and waste exchange between fetus and mother, as well as hormonal and immunological communication (1, 2). To meet the fetal requirements for nutrient and oxygen consumption during pregnancy, maternal cardiac output increases such that uteroplacental blood flow accounts for ϳ25% of total cardiac output (3). Glucose and oxygen are arguably the two most important molecules transferred from mother to fetus, in terms of both concentration and the multitude of physiological adaptations in place to ensure their adequate transport; however, the requirement for mitochondrial oxidative metabolism during embryonic development remains poorly defined.While oxygen tension in utero is low relative to atmospheric levels, measurement of oxygen consumption and lactate uptake in fetal lambs provided evidence that the fetus is a net consumer rather than a producer of lactate (4). Consistent with this, fetal myocardium consumes a large amount of lactate, in addition to glucose, indicating that oxidative metabolism of carbohydrates is an important energy source in the developing heart (5, 6). Additionally, lactate utilization is high in the neonatal brain, and the capacity for lactate import is higher in the neonatal brain than in the adult brain (7). Together, these observations provide evidence for the importance of mitochondrial oxidative metabolism early in mammalian development. S...

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Section: Mpc Deficiency Promotes Metabolic Plasticity In Uterosupporting

confidence: 91%

Requirement for the Mitochondrial Pyruvate Carrier in Mammalian Development Revealed by a Hypomorphic Allelic Series

Bowman

Zhao

Hartung

et al. 2016

Molecular and Cellular Biology

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“…There are two isoforms of PCK: cytosolic PCK (PCK1) and a mitochondrial isoform of PCK (PCK2). PCK1, but not PCK2, was reported to be over-expressed in colorectal cancer and promotes tumour growth by increasing glucose and glutamine metabolism52. PCK2 expression was reported to be elevated in non-small-cell lung carcinoma (NSCLC) and is regulated by glucose and required for in vivo tumour growth53.…”

Section: Discussionmentioning

confidence: 99%

Quantitative proteomics by SWATH-MS reveals sophisticated metabolic reprogramming in hepatocellular carcinoma tissues

Gao

Wang

Sang

et al. 2017

Sci Rep

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Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and understanding its molecular pathogenesis is pivotal to managing this disease. Sequential window acquisition of all theoretical mass spectra (SWATH-MS) is an optimal proteomic strategy to seek crucial proteins involved in HCC development and progression. In this study, a quantitative proteomic study of tumour and adjacent non-tumour liver tissues was performed using a SWATH-MS strategy. In total, 4,216 proteins were reliably quantified, and 338 were differentially expressed, with 191 proteins up-regulated and 147 down-regulated in HCC tissues compared with adjacent non-tumourous tissues. Functional analysis revealed distinct pathway enrichment of up- and down-regulated proteins. The most significantly down-regulated proteins were involved in metabolic pathways. Notably, our study revealed sophisticated metabolic reprogramming in HCC, including alteration of the pentose phosphate pathway; serine, glycine and sarcosine biosynthesis/metabolism; glycolysis; gluconeogenesis; fatty acid biosynthesis; and fatty acid β-oxidation. Twenty-seven metabolic enzymes, including PCK2, PDH and G6PD, were significantly changed in this study. To our knowledge, this study presents the most complete view of tissue-specific metabolic reprogramming in HCC, identifying hundreds of differentially expressed proteins, which together form a rich resource for novel drug targets or diagnostic biomarker discovery.

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“…For example, the mitochondrial isoform of PEPCK, PEPCK-M (also known as PCK2), which is expressed in breast and lung cancer cells, as well as in several other cancer cell lines, was reported to be increased and activated under limited glucose conditions 95–97 . It was also reported that the cytosolic form of PEPCK, PEPCK-C (also known as PCK1) is overexpressed in colon cancer, and it accelerates the generation of glycolytic intermediates 98 . Surprisingly, cytoplasmic PEPCK-C also increased the use of glucose by a mechanism that may involve the activation of mTORC1 that is not fully understood.…”

Section: Reprogramming Of Glucose Metabolismmentioning

confidence: 99%

Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy?

2016

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In recent years there has been a growing interest among cancer biologists in cancer metabolism. This Review summarizes past and recent advances in our understanding of the reprogramming of glucose metabolism in cancer cells, which is mediated by oncogenic drivers and by the undifferentiated character of cancer cells. The reprogrammed glucose metabolism in cancer cells is required to fulfil anabolic demands. This Review discusses the possibility of exploiting the reprogrammed glucose metabolism for therapeutic approaches that selectively target cancer cells.

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PEPCK Coordinates the Regulation of Central Carbon Metabolism to Promote Cancer Cell Growth

Cited by 195 publications

References 33 publications

Requirement for the Mitochondrial Pyruvate Carrier in Mammalian Development Revealed by a Hypomorphic Allelic Series

Requirement for the Mitochondrial Pyruvate Carrier in Mammalian Development Revealed by a Hypomorphic Allelic Series

Quantitative proteomics by SWATH-MS reveals sophisticated metabolic reprogramming in hepatocellular carcinoma tissues

Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy?

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