Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate
Open accessAbstract
Cancer metabolism has long been equated with aerobic glycolysis, seen by early biochemists as primitive and inefficient. Despite these early beliefs, the metabolic signatures of cancer cells are not passive responses to damaged mitochondria, but result from oncogene-directed metabolic reprogramming required to support anabolic growth. Recent evidence suggests that metabolites themselves can be oncogenic by altering cell signaling and blocking cellular differentiation. No longer can cancer-associated alterations in metabolism be viewed as an indirect response to cell proliferation and survival signals. We contend that altered metabolism has attained the status of a core hallmark of cancer.
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Written from the paper’s full text.
TL;DR
This review argues that metabolic reprogramming is a core hallmark of cancer, driven by oncogenes and tumor suppressors to support anabolic growth rather than arising passively from mitochondrial damage. It highlights mitochondrial biosynthetic roles, PKM2 and other metabolic enzyme alterations, and oncometabolites such as 2HG that can disrupt epigenetics and differentiation.
Key findings
- Altered metabolism is not merely a secondary response to proliferation signals; it results from active reprogramming by oncogenes and tumor suppressors and is selected during tumorigenesis. Most tumor mitochondria are not defective in oxidative phosphorylation, contrary to Warburg’s original hypothesis.
- PI3K/Akt/mTORC1 and Myc reprogram mitochondrial metabolism for biosynthesis: Akt activates ACL to divert mitochondrial citrate to acetyl-CoA, mTORC1 promotes mitochondrial biogenesis and SREBP-mediated lipogenesis, and Myc enhances glutaminase expression and glutamine addiction. HIF-1 can inhibit PDH via PDK1, blocking glucose carbon entry into mitochondrial citrate and correlating with anti-proliferative effects in some contexts.
- PKM2 is the predominant pyruvate kinase isoform in embryonic tissues and all cancer cells examined to date; it has intrinsically lower enzymatic activity than PKM1 and is sensitive to tyrosine kinase inhibition, proposed to facilitate shunting of glycolytic intermediates into anabolic pathways. At least 11 proteins have been reported to bind PKM2.
- IDH1/IDH2 mutations produce the oncometabolite 2HG, which inhibits α-ketoglutarate-dependent dioxygenases including TET enzymes and histone demethylases, altering DNA and histone methylation and impairing differentiation. IDH2 R140 mutations now account for nearly half of all cases of D-2HG aciduria; succinate and fumarate are also described as oncometabolites.
Methods
- Design: Review article; no primary experimental design is reported.
- Data or sample: Not stated in the paper as a primary dataset; the text synthesizes cited studies across cancer metabolism, oncogene/tumor suppressor signaling, metabolic enzyme isoforms, and oncometabolite biology.
- Main analysis: Conceptual and literature-based synthesis arguing that metabolic reprogramming should be considered a core cancer hallmark.
Limitations
- The paper states that current methods cannot reliably distinguish cytosolic metabolites from mitochondrial and other compartmentalized pools; fractionation methods often cause metabolite leakage, and distinct metabolite pools may exist due to enzyme channeling.
- The paper states that quantitative measurement of metabolic flux remains challenging, including obstacles such as cellular compartmentalization and reliance on complex, incompletely defined cell culture media.
- The paper states that non-cell autonomous effects of tumor metabolism are an emerging challenge, including lactate acidification, possible symbiosis between lactate-producing and lactate-consuming cells, and fatty acid exchange between omental adipocytes and ovarian carcinoma cells. The text also makes evident that unresolved issues remain, such as conflicting conclusions over whether reductive glutamine flux depends primarily on cytosolic IDH1 or mitochondrial IDH2, the role of 2HG in PHD2/HIF regulation, and which alternative NADPH-generating pathways are most important.
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Claims the paper makes
0 of 80 cited sources checked · 0 supported · 0 flagged
- Interpretationnone given
Evidence is developing for the proposal that proto-oncogenes and tumor suppressors primarily evolved to regulate metabolism.
“Evidence is also developing for the proposal that proto-oncogenes and tumor suppressors primarily evolved to regulate metabolism.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Altered metabolism has attained the status of a core hallmark of cancer.
“We contend that altered metabolism has attained the status of a core hallmark of cancer.”
Quote in the paperNot a substantial claim - Interpretationnone given
The metabolic signatures of cancer cells are not passive responses to damaged mitochondria, but result from oncogene-directed metabolic reprogramming required to support anabolic growth.
“Despite these early beliefs, the metabolic signatures of cancer cells are not passive responses to damaged mitochondria, but result from oncogene-directed metabolic reprogramming required to support anabolic growth.”
Quote in the paperNot a substantial claim - Premisecitation
Activated PI3K/Akt leads to enhanced glucose uptake and glycolysis.
“Activated PI3K/Akt leads to enhanced glucose uptake and glycolysis (Buzzai et al., 2005; Elstrom et al., 2004).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisenone given
Most cancer cells and proliferating normal cells still derive a significant fraction of their ATP through oxidative phosphorylation.
“In fact, most cancer cells and proliferating normal cells still derive a significant fraction of their ATP through oxidative phosphorylation.”
Quote in the paperNot a substantial claim
- Interpretationnone given
Metabolites themselves can be oncogenic by altering cell signaling and blocking cellular differentiation.
“Recent evidence suggests that metabolites themselves can be oncogenic by altering cell signaling and blocking cellular differentiation.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Proliferating cells are in much greater need of reduced carbon and reduced nitrogen, as well as cytosolic NADPH for reductive biosynthetic reactions, than of ATP.
“Rather than ATP, proliferating cells are in much greater need of reduced carbon and reduced nitrogen, as well as cytosolic NADPH for reductive biosynthetic reactions.”
Quote in the paperNot a substantial claim - Premisereasoning
Damaged mitochondria are not at the root of the aerobic glycolysis exhibited by most tumor cells.
“However, in contrast to Warburg's original hypothesis, damaged mitochondria are not at the root of the aerobic glycolysis exhibited by most tumor cells.”
Quote in the paperNot a substantial claim - Interpretationnone given
Strong evidence supports an alternative model in which changes in metabolic fluxes occur in primary response to growth factor signaling, independent of changes in ATP and other mechanisms.
“In this supply-based model, changes in metabolic fluxes occur in primary response to growth factor signaling, independent of changes in ATP and other mechanisms worked out by early biochemists (Figure 2B).”
Quote in the paperNot a substantial claim - Premisenone given
Most tumor mitochondria are not defective in their ability to carry out oxidative phosphorylation.
“Most tumor mitochondria are not defective in their ability to carry out oxidative phosphorylation.”
Quote in the paperNot a substantial claim - Interpretationnone given
Evidence for the concept that the primary functions of activated oncogenes and inactivated tumor suppressors are to reprogram cellular metabolism has continued to build.
“But evidence for an alternative concept, that the primary functions of activated oncogenes and inactivated tumor suppressors are to reprogram cellular metabolism, has continued to build over the past several years.”
Quote in the paperNot a substantial claim - Interpretationnone given
In proliferating cells, mitochondrial metabolism is reprogrammed to meet the challenges of macromolecular synthesis.
“Instead, in proliferating cells mitochondrial metabolism is reprogrammed to meet the challenges of macromolecular synthesis.”
Quote in the paperNot a substantial claim - Interpretationnone given
In proliferating cells, oxidative phosphorylation-dependent production of ATP appears secondary to the use of mitochondrial enzymes in the synthesis of anabolic precursors.
“However, in proliferating cells, in contrast to quiescent cells, this oxidative phosphorylation-dependent production of ATP appears secondary to the use of mitochondrial enzymes in the synthesis of anabolic precursors.”
Quote in the paperNot a substantial claim - Interpretationreasoning
The PI3K/Akt pathway promotes glucose carbon flux into biosynthetic pathways that rely upon functional mitochondrial metabolism.
“However, the PI3K/Akt pathway also promotes glucose carbon flux into biosynthetic pathways that rely upon functional mitochondrial metabolism (Figure 3).”
Quote in the paperSubstantial claim - Interpretationreasoning
Reprogramming of cellular metabolism towards macromolecular synthesis is critical to supplying enough nucleotides, proteins, and lipids for a cell to double its total biomass and then divide.
“The reprogramming of cellular metabolism towards macromolecular synthesis is critical to supplying enough nucleotides, proteins, and lipids for a cell to double its total biomass and then divide to produce two daughter cells.”
Quote in the paperSubstantial claim - Interpretationreasoning
Anabolic metabolism fundamental to cell growth and proliferation is not focused on maximizing ATP yield.
“In contrast to the catabolic metabolism of differentiated cells, this anabolic metabolism fundamental to cell growth and proliferation is not focused on maximizing ATP yield.”
Quote in the paperSubstantial claim - Premisecitation
SREBP-mediated de novo lipogenesis is a critical component of mTORC1-driven proliferation.
“Finally, a study isolating the cell-intrinsic consequences of mTORC1 activation demonstrated that SREBP-mediated de novo lipogenesis is a critical component of mTORC1-driven proliferation (Duvel et al., 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Duvel et al., 2010 source
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- Premisecitation
There is a lack of evidence that 2HG acts as a mutagen.
“the lack of evidence that 2HG was acting as a mutagen (Mardis et al., 2009)”
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AML samples with low to undetectable 2HG are IDH1 and IDH2 wild-type.
“AML samples with low to undetectable 2HG were subsequently sequenced and determined to be IDH1 and IDH2 wild-type”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Gross et al., 2010 source
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- Premisenone given
Some cancers exhibit decreased flux of glucose-derived pyruvate into the mitochondria relative to normal tissues.
“There are cancers which do exhibit decreased flux of glucose-derived pyruvate into the mitochondria relative to normal tissues.”
Quote in the paperSubstantial claim - Interpretationcitation
Oncogenic mutations in proto-oncogenes can be selected for in tumor populations subjected to metabolic stress.
“Oncogenic mutations in proto-oncogenes can be selected for in tumor populations subjected to metabolic stress.”
Quote in the paperSubstantial claim - Premisecitation
Neomorphic mutations of IDH1 or IDH2 and TET2 loss-of-function mutations are mutually exclusive in a large AML cohort.
“neomorphic mutations of IDH1 or IDH2 and TET2 loss-of-function mutations were found to be mutually exclusive in a large AML cohort”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Figueroa et al., 2010 source
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- Premisecitation
Additional IDH mutations can produce 2HG.
“additional IDH mutations can produce 2HG (Ward et al., 2011)”
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shRNA knockdown of TET2 recapitulates the effect of IDH mutant overexpression on blocking hematopoietic cell differentiation.
“shRNA knockdown of TET2 recapitulated the effect of IDH mutant overexpression on blocking hematopoietic cell differentiation (Figueroa et al., 2010)”
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IDH mutant expression and 2HG elevation can inhibit the TET family of enzymes that hydroxylate 5'-methylcytosine.
“multiple groups have found that IDH mutant expression and 2HG elevation can inhibit the TET family of enzymes that hydroxylate 5’-methylcytosine (Figueroa et al., 2010; Turcan et al., 2012; Xu et al., 2011)”
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- cites Turcan et al., 2012
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- cites Xu et al., 2011
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IDH2 R172 mutations result in 2HG elevation in primary AML samples.
“Enzymatic assays and measurement of 2HG levels in primary AML samples confirmed that these IDH2 R172 mutations result in 2HG elevation (Gross et al., 2010; Ward et al., 2010).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationcitation
The strongest evidence to date that altered metabolism is selected for by cancer cells during tumorigenesis has come with the recent elucidation of somatic mutations in metabolic enzymes.
“The strongest evidence to date that altered metabolism is selected for by cancer cells during tumorigenesis has come with the recent elucidation of somatic mutations in metabolic enzymes.”
Quote in the paperSubstantial claim - Interpretationreasoning
Reprogramming of mitochondrial citrate metabolism is a central aspect of PI3K/Akt oncogenic activity.
“Taken together, these findings demonstrate that the reprogramming of mitochondrial citrate metabolism is a central aspect of PI3K/Akt oncogenic activity.”
Quote in the paperSubstantial claim - Interpretationreasoning
Most cancers depend on syntheses of amino acid precursors from mitochondrial intermediates rather than exogenous supplies.
“Most cancers depend on these syntheses rather than exogenous supplies.”
Quote in the paperSubstantial claim - Interpretationcitation
Reprogrammed glutamine metabolism is critical to the growth and survival of Myc-driven malignancies.
“These data provide further evidence that reprogrammed glutamine metabolism is critical to the growth and survival of Myc-driven malignancies.”
Quote in the paperSubstantial claim - Premisecitation
HIF-1 activation inhibits mitochondrial metabolism of glucose carbon, in part by promoting expression of PDK1 to inhibit PDH activity.
“However, HIF-1 activation has the additional effect of inhibiting mitochondrial metabolism of glucose carbon, in part by promoting the expression of pyruvate dehydrogenase kinase 1 (PDK1) to inhibit PDH activity (Kim et al., 2006; Papandreou et al., 2006).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning
These cancers still rely on mitochondrial metabolic flux.
“However, as will be discussed later in this review, these cancers still rely on mitochondrial metabolic flux.”
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Serum 2HG levels correlate with IDH1 R132 mutations in AML.
“serum 2HG levels have successfully correlated with IDH1 R132 mutations in AML”
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1H magnetic resonance spectroscopy can be applied for 2HG detection in vivo for glioma.
“recent data have suggested that 1H magnetic resonance spectroscopy can be applied for 2HG detection in vivo for glioma (Andronesi et al., 2012; Choi et al., 2012; Gross et al., 2010; Pope et al., 2012)”
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TET2 mutant AML samples display an overlapping DNA hypermethylation signature with samples having IDH1 or IDH2 mutations.
“TET2 mutant AML samples displayed an overlapping DNA hypermethylation signature with samples having IDH1 or IDH2 mutations”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Figueroa et al., 2010 source
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- Interpretationcitation
Reduced pyruvate kinase enzymatic activity in the cytoplasm, leading to enhanced anabolic metabolism from glycolytic intermediates, is the primary role for PKM2 expression in proliferating cells.
“However, other studies have added further strength to the concept that reduced pyruvate kinase enzymatic activity in the cytoplasm, leading to enhanced anabolic metabolism from glycolytic intermediates, is the primary role for PKM2 expression in proliferating cells.”
Quote in the paperSubstantial claim - Premisecitation
IDH2 R172 mutations occur in a small fraction of gliomas lacking IDH1 mutations.
“a small fraction of gliomas lacking IDH1 mutations were known to harbor mutations at IDH2 R172, the analogous residue to IDH1 R132 (Yan et al., 2009)”
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Additional IDH alleles may account for the subset of 2HG-elevated chondrosarcoma samples that lacked common IDH1 or IDH2 mutations but were not examined for other IDH alterations.
“These additional alleles may account for the recently described subset of 2HG-elevated chondrosarcoma samples that lacked the most common IDH1 or IDH2 mutations but were not examined for other IDH alterations (Amary et al., 2011).”
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Proliferating cells almost universally express the M2 isoform of pyruvate kinase M (PKM2).
“For example, proliferating cells almost universally express the M2 isoform of pyruvate kinase M (PKM2).”
Quote in the paperSubstantial claim - Interpretationcitation
The weight of evidence suggests that regulation of HIF-1 stability through decreased PHD2 activity is not the primary effect of IDH mutations.
“The weight of the evidence now suggests that regulation of HIF-1 stability through decreased PHD2 activity is not the primary effect of IDH mutations (Chowdhury et al., 2011; Dang et al., 2009; Jin et al., 2011; Mardis et al., 2009; Metellus et al., 2011; Williams et al., 2011).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Oncogenic Myc promotes mitochondrial utilization of glutamine by enhancing expression of GLS.
“Oncogenic Myc has also been shown to promote the mitochondrial utilization of glutamine by enhancing the expression of glutaminase (GLS), which deamidates glutamine to glutamate.”
Quote in the paperSubstantial claim - Interpretationreasoning
2HG production is the primary feature being selected for in tumors.
“This discovery provided additional evidence that 2HG production was the primary feature being selected for in tumors.”
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IDH mutations occur early in disease progression.
“the finding that IDH mutations occurred early in disease progression (Watanabe et al., 2009)”
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- Interpretationnone given
Metabolic changes associated with proliferating cells do not simply occur passively in response to damaged mitochondria or changes in ATP levels.
“Metabolic changes associated with proliferating cells do not simply occur passively in response to damaged mitochondria or changes in ATP levels.”
Quote in the paperNot a substantial claim - Interpretationnone given
The weight of evidence supports the concept that reprogramming of cellular metabolism is a primary and fundamental aspect of transformation resulting from mutations in proto-oncogenes and tumor suppressors.
“The weight of the evidence to date supports the concept that reprogramming of cellular metabolism is a primary and fundamental aspect of transformation resulting from mutations in proto-oncogenes and tumor suppressors.”
Quote in the paperNot a substantial claim - Premisecitation
2HG can inhibit several α-ketoglutarate dependent dioxygenase enzymes.
“Numerous reports have now highlighted the ability of 2HG to inhibit several α-ketoglutarate dependent dioxygenase enzymes (Figure 5).”
Quote in the paperSubstantial claim - Premisecitation
The common feature of the remaining subset of 2HG-elevated AMLs is another mutation in IDH2 at R140.
“the common feature of this remaining subset of 2HG-elevated AMLs was another mutation in IDH2, occurring at R140 (Ward et al., 2010)”
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Several AML samples with elevated 2HG have neomorphic mutations at either IDH1 R132 or IDH2 R172.
“several samples with elevated 2HG were found to have neomorphic mutations at either IDH1 R132 or IDH2 R172 (Gross et al., 2010)”
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These cancers preferentially perform reductive and carboxylating biosynthetic reactions from glutamine carbon in place of oxidative metabolism of both glucose and glutamine.
“In place of oxidative metabolism of both glucose and glutamine, these cancers preferentially perform reductive and carboxylating biosynthetic reactions from glutamine carbon (Le et al., 2012; Metallo et al., 2012; Mullen et al., 2012; Wise et al., 2011).”
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2HG is a rare metabolite found at only trace amounts in mammalian cells under normal conditions.
“a rare metabolite found at only trace amounts in mammalian cells under normal conditions (Dang et al., 2009)”
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Some 2HG-elevated AML samples lack IDH1 R132 or IDH2 R172 mutations.
“some 2HG-elevated AML samples lacked IDH1 R132 or IDH2 R172 mutations”
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By diverting pyruvate into lactate, HIF-1 blocks glucose carbon incorporation into mitochondrial citrate which is critical for lipid synthesis.
“By diverting pyruvate into lactate, HIF-1 blocks glucose carbon incorporation into mitochondrial citrate which is critical for lipid synthesis (Lum et al., 2007).”
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- Interpretationnone given
Proliferative metabolism is heavily dependent on the reprogramming of mitochondria to serve a synthetic rather than degradative role.
“Proliferative metabolism is heavily dependent on the reprogramming of mitochondria to serve a synthetic rather than degradative role.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Current evidence suggests the decreased activity of PKM2 is selected to facilitate anabolic metabolism.
“Current evidence suggests the decreased activity of PKM2 is selected to facilitate anabolic metabolism (Figure 4).”
Quote in the paperSubstantial claim - Interpretationnone given
Increased glycolytic metabolism from activated Ras does not stem from defective mitochondrial pathways.
“Importantly, increased glycolytic metabolism from activated Ras does not stem from defective mitochondrial pathways.”
Quote in the paperSubstantial claim - Premisecitation
Tumor cells have a propensity to synthesize pentose phosphates through a G6PD-independent pathway.
“the observed propensity of tumor cells to synthesize pentose phosphates through a G6PD-independent pathway (Boros et al., 2000; Zhao et al., 2010)”
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In gliomas and chondrosarcomas there is no evidence of mutations in TET enzymes.
“in gliomas and chondrosarcomas there is no evidence of mutations in TET enzymes”
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In human cells proliferating in hypoxia, α-ketoglutarate can accumulate and be metabolized through enhanced reductive activity of wild-type IDH2 in mitochondria, leading to 2HG accumulation in the absence of IDH mutation.
“in human cells proliferating in hypoxia, α-ketoglutarate can accumulate and be metabolized through an enhanced reductive activity of wild-type IDH2 in the mitochondria, leading to 2HG accumulation in the absence of IDH mutation (Wise et al., 2011)”
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Succinate alters histone demethylase activity in yeast.
“succinate has been shown to alter histone demethylase activity in yeast (Smith et al., 2007)”
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Cohort studies have not detected a decrease in cancer incidence in G6PD-deficient men.
“cohort studies have not detected a decrease in cancer incidence in G6PD-deficient men (Cocco et al., 1998; Ferraris et al., 1988)”
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- cites Ferraris et al., 1988
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Fumarate can inhibit PHD2.
“Subsequent work confirmed that fumarate could inhibit PHD2 (Isaacs et al., 2005)”
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In immortalized astrocytes, IDH mutation causes progressive accumulation of H3K9 methylation that precedes increase in DNA methylation.
“there was a progressive accumulation of H3K9 methylation which preceded the increase in DNA methylation”
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IDH-dependent reductive carboxylation has been investigated as a way to produce citrate and fatty acids from α-ketoglutarate derived from glutamine.
“has been investigated since then as a way to produce citrate and fatty acids from α-ketoglutarate derived from glutamine (Holleran et al., 1995; Ward et al., 2010; Yoo et al., 2008)”
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The mark most altered with stable, as opposed to transient, expression of IDH mutation is methylation at histone H3 lysine 9 (H3K9).
“the mark most altered with stable, as opposed to transient, expression of IDH mutation is methylation at histone H3 lysine 9 (H3K9) (Lu et al., 2012)”
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IDH-dependent reductive carboxylation plays a particularly important role in proliferating cells that exhibit decreased flux of glucose-derived pyruvate into mitochondria, in hypoxic cells or cells with defects in mitochondrial oxidative phosphorylation.
“Recently three independent reports implicated IDH-dependent reductive carboxylation as playing a particularly important role in proliferating cells that exhibit decreased flux of glucose-derived pyruvate into the mitochondria. This occurs in hypoxic cells or in cells harboring defects in mitochondrial oxidative phosphorylation (Metallo et al., 2012; Mullen et al., 2012; Wise et al., 2011).”
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Glucose carbon is important to be metabolized through other branches of glycolytic metabolism, including serine synthesis and the hexosamine pathway.
“It would also fit with the importance of glucose carbon to be metabolized through other branches of glycolytic metabolism, including serine synthesis (as discussed above) and the hexosamine pathway (Wellen et al., 2010).”
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R(-)-2HG (D-2HG) is the exclusive 2HG stereoisomer produced by IDH1 and IDH2 mutants.
“R(-)-2HG (also known as D-2HG) is the exclusive 2HG stereoisomer produced by IDH1 and IDH2 mutants (Dang et al., 2009; Ward et al., 2010)”
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2HG can inhibit the prolyl hydroxylase that regulates collagen synthesis.
“2HG can inhibit the prolyl hydroxylase that regulates collagen synthesis (Xu et al., 2011)”
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NADH can be converted to NADPH within mitochondria via a transhydrogenase absent from the cytosol.
“NADH can be converted to NADPH within the mitochondria via a transhydrogenase absent from the cytosol (Rydstrom, 2006)”
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Smaller case control studies have failed to demonstrate a relationship between G6PD deficiency and cancer.
“smaller case control studies have also failed to demonstrate a relationship (Forteleoni et al., 1988; Pisano et al., 1991)”
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IDH2 R140 mutations account for nearly half of all cases of D-2HG aciduria.
“IDH2 R140 mutations now account for nearly half of all cases of this devastating disease (Kranendijk et al., 2010)”
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Loss-of-function mutations in the TCA cycle enzymes succinate dehydrogenase (SDH) and fumarate hydratase (FH) occur in pheochromocytoma, paraganglioma, leiomyoma, and renal carcinoma.
“Loss of function mutations in the TCA cycle enzymes succinate dehydrogenase (SDH) and fumarate hydratase (FH) have been known for several years to occur in pheochromocytoma, paraganglioma, leiomoyoma, and renal carcinoma.”
Quote in the paperSubstantial claim - Premisecitation
For many proliferating cells, the major problem is not how to maximize ATP yield, but rather how to maximize the flux of carbon into macromolecular synthetic pathways.
“for many proliferating cells, the major problem is not how to maximize ATP yield, but rather how to maximize the flux of carbon into macromolecular synthetic pathways”
Quote in the paperSubstantial claim - Interpretationreasoning
Reductive flux is likely to occur in the mitochondria.
“knowledge regarding cellular redox suggests the reductive flux is likely to occur in the mitochondria”
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Mitochondria have a high NADH:NAD+ ratio, particularly in hypoxia.
“Mitochondria have a high NADH:NAD+ ratio, particularly in hypoxia (Chance and Thorell, 1959; Frezza et al., 2011)”
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2HG-induced alterations in histone and DNA methylation are likely synergistic.
“The 2HG-induced alterations in histone and DNA methylation are likely synergistic”
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Succinate can inhibit PHD3.
“and that succinate could also inhibit the related enzyme PHD3 (Lee et al., 2005)”
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In gliomas and chondrosarcomas, IDH1 or IDH2 mutations are linked with altered DNA methylation profiles.
“in gliomas and chondrosarcomas IDH1 or IDH2 mutations have been linked with altered DNA methylation profiles (Noushmehr et al., 2010; Pansuriya et al., 2011; Turcan et al., 2012)”
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Cells with activated PI3K/Akt upregulate the activity of ENTPD5, an endoplasmic reticulum enzyme involved in glycosylation reactions and linked to ATP hydrolysis.
“cells with activated PI3K/Akt upregulate the activity of ENTPD5, an endoplasmic reticulum enzyme involved in glycosylation reactions and linked to ATP hydrolysis (Fang et al., 2010)”
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Neoplastic clones in females with mosaicism for the Mediterranean variant of G6PD did not demonstrate preferential expression of the wild type G6PD allele.
“Neoplastic clones did not demonstrate preferential expression of the wild type G6PD allele.”
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Inhibition of H3K9 demethylation by 2HG, or siRNA knockdown of an H3K9 demethylase, is sufficient to block cell differentiation in the absence of changes in DNA methylation.
“inhibition of H3K9 demethylation by 2HG, or siRNA knockdown of an H3K9 demethylase, was sufficient to block cell differentiation in the absence of changes in DNA methylation”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lu et al., 2012
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- Interpretationnone given
Cytosolic NADPH might be limiting for cell proliferation.
“Unlike ATP, cytosolic NADPH might be limiting for cell proliferation.”
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Germline IDH2 R140 mutations occur in D-2HG aciduria.
“researchers looked for and successfully found germline IDH2 R140 mutations in D-2HG aciduria”
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Succinate impairs PHD2 through product inhibition.
“Succinate was initially found to impair PHD2, the α-ketoglutarate-dependent enzyme regulating HIF stability, through product inhibition (Selak et al., 2005).”
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These studies focused on men with the Mediterranean variant of G6PD, an allele demonstrating severe enzyme deficiency with less than 10 percent of normal activity.
“These studies focused on men with the Mediterranean variant of G6PD, an allele demonstrating severe enzyme deficiency with less than 10 percent of normal activity.”
Quote in the paperSubstantial claim - Interpretationreasoning
Elevated HIF levels in SDH- and FH-deficient tumors are linked to the activity of the succinate and fumarate metabolites.
“These observations linked the elevated HIF levels observed in SDH and FH deficient tumors to the activity of the succinate and fumarate metabolites.”
Quote in the paperSubstantial claim - Interpretationcitation
Inhibition of the prolyl hydroxylase that regulates collagen synthesis by 2HG could impact the tumor microenvironment and partly account for the diffuse nature of lower-grade gliomas.
“This inhibition could impact the tumor microenvironment and partly account for the diffuse nature of lower-grade gliomas.”
Quote in the paperSubstantial claim - Premisecitation
IDH-dependent reductive carboxylation of α-ketoglutarate to isocitrate was described in early metabolic literature.
“IDH-dependent reductive carboxylation of α-ketoglutarate to isocitrate was described in early metabolic literature (Ochoa, 1948)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ochoa, 1948 source
Not checked in the free run.
- Interpretationnone given
Altered metabolism results from active reprogramming by altered oncogenes and tumor suppressors.
“Data now support the concepts that altered metabolism results from active reprogramming by altered oncogenes and tumor suppressors”
Quote in the paperNot a substantial claim - Interpretationnone given
Metabolic adaptations can be clonally selected during tumorigenesis.
“and that metabolic adaptations can be clonally selected during tumorigenesis”
Quote in the paperNot a substantial claim
- Classified as probably not a substantial claim. 12
- May combine two claims. 14
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone givenActivation of the PI3K/Akt pathway is perhaps the most common lesion in spontaneous human cancers.
“Activation of the PI3K/Akt pathway is perhaps the most common lesion in spontaneous human cancers.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone givenAnabolic metabolism is under complex regulatory control directed by growth factor signal transduction in non-transformed cells.
“It has become clear that anabolic metabolism is under complex regulatory control directed by growth factor signal transduction in non-transformed cells.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningPKM2 primarily acts as a glycolytic switch that can be rapidly inactivated in tumor cells by multiple mechanisms, all of which facilitate the shunting of glucose carbon/glycolytic intermediates into branching anabolic pathways.
“Both of these findings are consistent with PKM2 primarily acting as a glycolytic switch that can be rapidly inactivated in tumor cells by multiple mechanisms, all of which facilitate the shunting of glucose carbon/glycolytic intermediates into branching anabolic pathways.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationIDH1 mutations at R132 are not simply loss-of-function for isocitrate and α-ketoglutarate interconversion; they also acquire a novel reductive activity converting α-ketoglutarate to 2-hydroxyglutarate (2HG).
“IDH1 mutations at R132 are not simply loss-of-function for isocitrate and α-ketoglutarate interconversion, but also acquire a novel reductive activity to convert α-ketoglutarate to 2-hydroxyglutarate (2HG)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Dang et al., 2009 source
Not checked in the free run.
May combine two claims.
PremisecitationOverexpression of IDH mutants blocks acquisition of mature myeloid markers while increasing expression of stem cell markers in 32D myeloid cells and mouse primary bone marrow cells cultured ex vivo.
“In both cell types, the overexpression of IDH mutants blocked acquisition of mature myeloid markers while increasing the expression of stem cell markers (Figueroa et al., 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Figueroa et al., 2010 source
Not checked in the free run.
May combine two claims.
PremisecitationMetabolite screening approaches can distinguish neomorphic IDH mutations from SNPs and sequencing artifacts with no effect on IDH enzyme activity, and from loss-of-function, non 2HG-producing IDH mutations.
“Metabolite screening approaches can also distinguish neomorphic IDH mutations from SNPs and sequencing artifacts with no effect on IDH enzyme activity, as well as from an apparently rare subset of loss-of-function, non 2HG-producing IDH mutations”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ward et al., 2011
Not checked in the free run.
May combine two claims.
PremisecitationCells expressing oncogenic Myc are glutamine-addicted and undergo apoptosis when glutamine is withdrawn from the culture medium.
“Cells expressing oncogenic Myc are glutamine-addicted and undergo apoptosis when glutamine is withdrawn from the culture medium.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
InterpretationreasoningSignificant flux through G6PD to generate NADPH is not necessarily critical for cell proliferation or tumorigenesis.
“these data raise the possibility that significant flux through G6PD to generate NADPH is not necessarily critical for cell proliferation or tumorigenesis”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Premisenone givenThe oxidative pentose phosphate pathway, branching off glycolysis at G6PD, has been considered the major NADPH producing pathway.
“Historically, the oxidative pentose phosphate pathway, branching off glycolysis at glucose-6-phosphate dehydrogenase (G6PD), has been considered the major NADPH producing pathway.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S4 (based). May combine two claims.
Premisenone givenNADPH is critical for providing reducing equivalents for fatty acid and cholesterol biosynthesis, as well as for modulating oxidative stress.
“It is critical for providing reducing equivalents for fatty acid and cholesterol biosynthesis, as well as for modulating oxidative stress.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S4 (based).
InterpretationreasoningA mitochondrial-cytosolic NADPH shuttle using IDH1 and IDH2 could reconcile conflicting conclusions about whether reductive flux of glutamine-derived carbon is primarily dependent on cytosolic IDH1 or mitochondrial IDH2.
“These findings could all be correct if a mitochondrial-cytosolic NADPH shuttle exists using these enzymes (Figure 6).”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationProliferating cells maintain glycolytic flux by either minimizing ATP production or enhancing ATP consumption.
“Recent work has revisited how proliferating cells maintain glycolytic flux by either minimizing ATP production or enhancing ATP consumption.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
InterpretationcitationElevated succinate and fumarate resulting from SDH and FH mutations can promote tumorigenesis in part through epigenetic modulation.
“Perhaps elevated succinate and fumarate resulting from SDH and FH mutations can promote tumorigenesis in part through epigenetic modulation.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningIDH mutation can impair differentiation in non-transformed cells from multiple cells of origin, and this impairment is linked to 2HG-mediated epigenetic dysregulation.
“these findings provide further evidence that IDH mutation can impair differentiation in non-transformed cells from multiple cells of origin, and that this impairment is linked to 2HG-mediated epigenetic dysregulation.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).
InterpretationreasoningThe ability of 2HG to alter epigenetics may reflect its evolutionary ancient status as a signal for elevated glutamine/glutamate metabolism and/or oxygen deficiency.
“The ability of 2HG to alter epigenetics may reflect its evolutionary ancient status as a signal for elevated glutamine/glutamate metabolism and/or oxygen deficiency.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
InterpretationreasoningOther chromatin-modifying α-ketoglutarate dependent dioxygenase enzymes may be inhibited by 2HG in glioma and chondrosarcoma cells.
“Alternatively, other chromatin-modifying α-ketoglutarate dependent dioxygenase enzymes may be inhibited by 2HG in these cells.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationIn the alternative glycolytic pathway, the high-energy phosphate of PEP is not transferred to ADP, but instead to a histidine residue on an upstream glycolytic enzyme, decoupling PEP→pyruvate conversion from ATP production.
“In this alternative pathway, the high-energy phosphate of PEP is not transferred to ADP, but instead to a histidine residue on an upstream glycolytic enzyme. This alternative transfer therefore decouples the PEP→pyruvate conversion from ATP production.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Vander Heiden et al., 2010
Not checked in the free run.
May combine two claims.
PremisecitationGlycolysis in proliferating cells is limited by the rate of ATP consumption and not ATP production, as glycolytic enzymes can be inhibited when ATP levels are high.
“glycolysis in proliferating cells is limited by the rate of ATP consumption and not ATP production, as glycolytic enzymes can be inhibited when ATP levels are high (Scholnick et al., 1973)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Scholnick et al., 1973
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone givenEven within one subcellular compartment, there may be distinct pools of metabolites resulting from channeling between metabolic enzymes.
“Even within one subcellular compartment, there may be distinct pools of metabolites resulting from channeling between metabolic enzymes.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisereasoningMany obstacles remain in quantitative measurement of metabolic flux, such as cellular compartmentalization and reliance of most cell culture on complex, incompletely defined media.
“many obstacles remain such as cellular compartmentalization and the reliance of most cell culture on complex, incompletely defined media.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisenone givenCurrent fractionation methods often lead to metabolite leakage, making it difficult to reliably distinguish cytosolic metabolites from those in mitochondria and other compartments.
“we remain unable to reliably distinguish cytosolic metabolites from those in the mitochondria and other compartments. Current fractionation methods often lead to metabolite leakage.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSome tumors may exhibit a symbiosis between lactate-producing cells and lactate-consuming cells.
“some tumors may exhibit a symbiosis between lactate-producing cells and lactate-consuming cells (Sonveaux et al., 2008)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sonveaux et al., 2008
Not checked in the free run.
May combine two claims.
PremisecitationLactate produced by tumor cells can acidify the surrounding microenvironment and potentially promote tumor invasion.
“lactate produced by tumor cells can acidify the surrounding microenvironment and potentially promote tumor invasion”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sonveaux et al., 2008
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationFatty acid exchange between omental adipocytes and ovarian carcinoma cells has been documented.
“fatty acid exchange between omental adipocytes and ovarian carcinoma cells has been documented (Nieman et al., 2011)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Nieman et al., 2011
Not checked in the free run.
May combine two claims.
PremisecitationCritical fluxes have been quantified in cultured cancer cells and methods for these analyses continue to improve.
“critical fluxes have been quantified in cultured cancer cells and methods for these analyses continue to improve (DeBerardinis et al., 2007; Mancuso et al., 2004; Yuan et al., 2008)”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites DeBerardinis et al., 2007 source
Not checked in the free run.
- cites Mancuso et al., 2004
Not checked in the free run.
- cites Yuan et al., 2008
Not checked in the free run.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Evidence for the necessity of glutamine for cancer progression is conflicted: some studies report tumours can grow well without glutamine, while others show cancers are glutamine-addicted.
“The evidence for the necessity of glutamine for cancer progression is conflicted: some studies have reported that tumours can grow well without glutamine [66,67], while others showed that cancers are glutamine-addicted [68,69,70].”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [68]
The previous paradigm argued metabolic pathways were exclusively controlled through allosteric regulation of metabolic enzymes by ATP or metabolites.
“The previous paradigm of metabolic regulation argued that metabolic pathways were exclusively controlled through allosteric regulation of metabolic enzymes, either by ATP levels or metabolites themselves (the reactive model) (40).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [40]
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Metabolic reprogramming for cancer cells and their microenvironment: Beyond the Warburg Effect
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- Authors
- Ward, P. S., & Thompson, C. B.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Thompson, Craig B.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 21
- Issue
- 3
- Pages
- 297-308
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3311998
- OpenAlex
- W2052543023
- Semantic Scholar
- 9802ecaa29613434cd7f6f7fa0e72b84a26c9d29
- Cited by
- 3,233
- References
- 145
- Citations by year
- 2026: 149 · 2025: 170 · 2024: 216 · 2023: 204 · 2022: 269 · 2021: 271 · 2020: 295 · 2019: 244 · 2018: 256 · 2017: 235 · 2016: 213 · 2015: 248 · 2014: 228 · 2013: 169 · 2012: 63
- FWCI
- 17.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 994 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Pennsylvania
- National Institutes of Health
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- cancer metabolism, metabolic reprogramming, aerobic glycolysis, Warburg effect, anabolic metabolism, signal transduction, cell differentiation, cancer hallmarks, mitochondrial damage
- MeSH terms
- Cell Differentiation, Humans, Isoenzymes, Mitochondria, Models, Biological, Neoplasms, Biomarkers, Tumor, Signal Transduction, Proto-Oncogene Proteins c-myc, Alternative Splicing, Evolution, Molecular, Epigenesis, Genetic, Cell Proliferation
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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