Glutaminolysis: Supplying carbon or nitrogen or both for cancer cells?

Dang, Chi V.

doi:10.4161/cc.9.19.13302

Cited by 212 publications

(170 citation statements)

References 22 publications

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“…17 Under normoxic conditions, the metabolism of glutamine (glutaminolysis) is a major part of the Warburg effect. 18 A high consumption of glutamine seems to be a general phenomenon during the rapid proliferation of most cell types. 17 Figure 1.…”

Section: Role Of Hif1 In Ph Regulationmentioning

confidence: 99%

“…21 By rethinking the Warburg effect, the amino acid glutamine seems to be very important for tumor cells. 18,22,23 An important consequence of glutaminolysis and the release of ammonia is a decrease of intracellular pH value (pH i ). 24,25 However, hypoxia always decreases the pH i value of the cell because of an alteration in the metabolic response (e.g., lactate and ammonia generation).…”

Section: Role Of Hif1 In Ph Regulationmentioning

confidence: 99%

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The real face of HIF1α in the tumor process

et al. 2012

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Section: Role Of Hif1 In Ph Regulationmentioning

confidence: 99%

Section: Role Of Hif1 In Ph Regulationmentioning

confidence: 99%

The real face of HIF1α in the tumor process

et al. 2012

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“…3) (DeBerardinis et al 2007;Dang 2010). Glutamine can provide carbon for lipid synthesis by oxidative metabolism through the TCA cycle to produce malate, which when converted to pyruvate can be decarboxylated to yield acetyl-coA in the mitochondria followed by export to the cytosol via the citrate shuttle.…”

Section: Glutamine Carbon Can Be Used As a Precursor For Lipid Synthesismentioning

confidence: 99%

“…Glutamine can provide carbon for lipid synthesis by oxidative metabolism through the TCA cycle to produce malate, which when converted to pyruvate can be decarboxylated to yield acetyl-coA in the mitochondria followed by export to the cytosol via the citrate shuttle. This route of glutamine metabolism, termed glutaminolysis, can fuel mitochondrial ATP generation, serve as a source of NADPH by the action of malic enzyme, and supply anapleurotic carbon to the TCA cycle (DeBerardinis et al 2007;Dang 2010). However, glutamine can also be used to generate cytosolic acetyl-coA via a reductive pathway involving direct conversion of a-ketoglutarate and CO 2 to citrate (Yoo et al 2008;Metallo et al 2011).…”

Section: Glutamine Carbon Can Be Used As a Precursor For Lipid Synthesismentioning

confidence: 99%

Metabolic Pathway Alterations that Support Cell Proliferation

Heiden

Lunt

Dayton

et al. 2011

Cold Spring Harbor Symposia on Quantitative Biology

259

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Proliferating cells adapt metabolism to support the conversion of available nutrients into biomass. How cell metabolism is regulated to balance the production of ATP, metabolite building blocks, and reducing equivalents remains uncertain. Proliferative metabolism often involves an increased rate of glycolysis. A key regulated step in glycolysis is catalyzed by pyruvate kinase to convert phosphoenolpyruvate (PEP) to pyruvate. Surprisingly, there is strong selection for expression of the less active M2 isoform of pyruvate kinase (PKM2) in tumors and other proliferative tissues. Cell growth signals further decrease PKM2 activity, and cells with less active PKM2 use another pathway with separate regulatory properties to convert PEP to pyruvate. One consequence of using this alternative pathway is an accumulation of 3-phosphoglycerate (3PG) that leads to the diversion of 3PG into the serine biosynthesis pathway. In fact, in some cancers a substantial portion of the total glucose flux is directed toward serine synthesis, and genetic evidence suggests that glucose flux into this pathway can promote cell transformation. Environmental conditions can also influence the pathways that cells use to generate biomass with the source of carbon for lipid synthesis changing based on oxygen availability. Together, these findings argue that distinct metabolic phenotypes exist among proliferating cells, and both genetic and environmental factors influence how metabolism is regulated to support cell growth.All cells rely on a source of nutrients for growth and survival. These nutrients are taken up from the environment and directed into metabolic pathways to maintain homeostasis and fuel cell-type-specific functions. For all cells, these processes include maintenance of ion gradients across membranes, transport of materials between intracellular compartments, and other housekeeping functions such as protein turnover. Many of these processes are thermodynamically unfavorable and thus are coupled to ATP hydrolysis as a source of free energy. To provide metabolic support for these functions, cells have evolved pathways, such as the oxidative metabolism of glucose, that when coupled to mitochondrial oxidative phosphorylation can efficiently generate ATP from available nutrients.Proliferating cells, including cancer cells, metabolize nutrients to support these same housekeeping functions. They also must take up additional nutrients, metabolize these nutrients through pathways that produce ATP, and generate all the components necessary to duplicate the mass of the cell and allow for cell division (Fig.

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“…All these results point to the enigmatic roles and underlying mechanisms for cMyc yet to be further elucidated under developmental or oncogenic circumstances. cMyc has been extensively documented to regulate glucose, glutamine and nucleotides metabolism [7,[40][41][42][43], nevertheless, it is unclear whether cMyc also controls the serine/glycine metabolism, especially under nutrient-deprived conditions.…”

Section: Introductionmentioning

confidence: 99%

cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions

et al. 2015

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Cancer cells are known to undergo metabolic reprogramming to sustain survival and rapid proliferation, however, it remains to be fully elucidated how oncogenic lesions coordinate the metabolic switch under various stressed conditions. Here we show that deprivation of glucose or glutamine, two major nutrition sources for cancer cells, dramatically activated serine biosynthesis pathway (SSP) that was accompanied by elevated cMyc expression. We further identified that cMyc stimulated SSP activation by transcriptionally upregulating expression of multiple SSP enzymes. Moreover, we demonstrated that SSP activation facilitated by cMyc led to elevated glutathione (GSH) production, cell cycle progression and nucleic acid synthesis, which are essential for cell survival and proliferation especially under nutrient-deprived conditions. We further uncovered that phosphoserine phosphatase (PSPH), the final rate-limiting enzyme of the SSP pathway, is critical for cMyc-driven cancer progression both in vitro and in vivo, and importantly, aberrant expression of PSPH is highly correlated with mortality in hepatocellular carcinoma (HCC) patients, suggesting a potential causal relation between this cMyc-regulated enzyme, or SSP activation in general, and cancer development. Taken together, our results reveal that aberrant expression of cMyc leads to the enhanced SSP activation, an essential part of metabolic switch, to facilitate cancer progression under nutrient-deprived conditions.

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Glutaminolysis: Supplying carbon or nitrogen or both for cancer cells?

Cited by 212 publications

References 22 publications

The real face of HIF1α in the tumor process

The real face of HIF1α in the tumor process

Metabolic Pathway Alterations that Support Cell Proliferation

cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions

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