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Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells
Open accessAbstract
The idea that conversion of glucose to ATP is an attractive target for cancer therapy has been supported in part by the observation that glucose deprivation induces apoptosis in rodent cells transduced with the proto-oncogene MYC, but not in the parental line. Here, we found that depletion of glucose killed normal human cells irrespective of induced MYC activity and by a mechanism different from apoptosis. However, depletion of glutamine, another major nutrient consumed by cancer cells, induced apoptosis depending on MYC activity. This apoptosis was preceded by depletion of the Krebs cycle intermediates, was prevented by two Krebs cycle substrates, but was unrelated to ATP synthesis or several other reported consequences of glutamine starvation. Our results suggest that the fate of normal human cells should be considered in evaluating nutrient deprivation as a strategy for cancer therapy, and that understanding how glutamine metabolism is linked to cell viability might provide new approaches for treatment of cancer.
Overview
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TL;DR
In human cells, glucose deprivation killed normal fibroblasts independently of MYC and not by apoptosis, whereas glutamine deprivation induced MYC-dependent apoptosis. The glutamine-dependent death was linked to depletion of Krebs cycle intermediates and was prevented by pyruvate or oxaloacetate, but not by ATP, glutathione, DNA damage, protein synthesis, or mTOR mechanisms.
Key findings
- Glucose depletion killed IER-MYC human fibroblasts irrespective of ERTM-MYC activity; 0.5 mM glucose (2% of normal) killed more slowly but also independently of MYC. Death was not apoptosis, as shown by absence of chromatin condensation and failure of Bcl-2 to prevent death.
- Glutamine depletion killed IER-MYC cells faster when ERTM-MYC was active; IER control cells remained viable without glutamine regardless of OHT. Death was apoptosis via the intrinsic pathway: Bcl-2 and caspase-9 dominant-negative prevented death, while crmA had no effect.
- Apoptosis after glutamine depletion was not caused by ATP deficiency, glutathione deficiency, DNA damage, protein synthesis deficiency, mTOR inhibition, or cell cycle arrest. Glutamine deprivation depleted Krebs cycle intermediates except citrate and isocitrate; pyruvate or oxaloacetate completely prevented apoptosis but did not restore proliferation, and the NADH/NAD ratio remained unchanged.
- Nutrient requirements varied by cell type: HFF-ER-MYC reacted like IER-MYC; HA1E cells underwent apoptosis after glucose depletion and reacted to glutamine depletion like IER-MYC; RPE-hTERT cells survived without glutamine irrespective of ectopic MYC and died without glucose independently of MYC by a non-apoptotic mechanism.
Methods
- Normal human fibroblasts IMR90 were retrovirally transduced with ERTM-MYC (IER-MYC) or ERTM alone (IER); HFF, HA1E, and RPE-hTERT cells were also tested. ERTM-MYC was activated with 200 nM 4-hydroxytamoxifen (OHT), with ethanol as vehicle.
- Nutrient depletion used glucose-free or glutamine-free DMEM; standard concentrations were 10 mM glucose and 2 mM glutamine. Viability and apoptosis were assessed by annexin V/PI, Hoechst 33342 nuclear morphology, Trypan Blue, and immunoblotting/immunofluorescence.
- Metabolite and viability analyses included ATP by luciferin-luciferase, reduced glutathione by flow cytometry, NADH/NAD by enzymatic cycling, lactate by LDH reaction, and capillary electrophoresis coupled to mass spectrometry (CE-MS) for metabolite profiling. Results are presented as averages of independent experiments with SDs where indicated.
Limitations
- Stated: how abnormal MYC synergizes with glutamine depletion to induce apoptosis remains to be determined; the authors cannot exclude a combination of tested mechanisms or an unknown glutamine function. Mitochondrial NADH/NAD+ and FADH/FAD+ ratios were not measured.
- Stated: the effect of nutrient depletion varied across cell types, so conclusions may be difficult to extrapolate from one or a few experimental systems.
- Evident: the study relies on ectopically expressed inducible ERTM-MYC in cultured human cell lines rather than endogenous MYC or in vivo tumor models; several supporting observations are described as unpublished or are based on two independent experiments.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“depletion of glucose killed normal human cells irrespective of induced MYC activity and by a mechanism different from apoptosis.”
- Also stated in: § Glucose deprivation kills normal human fibroblasts not by apoptosis and largely independently of the MYC activity · plain
“depletion of glucose killed IER-MYC cells irrespective of ERTM-MYC activity (Fig. 1, A and B).”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Glucose deprivation kills normal human fibroblasts not by apoptosis and largely independently of the MYC activity · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“by a mechanism different from apoptosis.”
- Also stated in: § Glucose deprivation kills normal human fibroblasts not by apoptosis and largely independently of the MYC activity · hedged
“cells in our system died by a process other than apoptosis, as indicated by the absence of characteristic chromatin condensation (Fig. 1 C) and the failure of Bcl-2, an inhibitor of apoptosis, to prevent cell death (Fig. 1 D).”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Glucose deprivation kills normal human fibroblasts not by apoptosis and largely independently of the MYC activity · hedged
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“glutamine depletion even prevented the increase in p53 concentration caused by activation of ERTM-MYC”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Discussion > How does ectopic activity of MYC synergize with glutamine depletion to induce apoptosis?
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Apoptosis was induced through the intrinsic pathway because Bcl-2 and a caspase-9 dominant-negative mutant (C9DN) prevented death (Fig. 3, A and B), whereas crmA, a viral inhibitor of the extrinsic pathway (Enari et al., 1995), had no effect (Fig. 3 D).”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Results > Glutamine deprivation induces apoptosis selectively in cells with acutely activated ER-MYC
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the antioxidants that we tested, tiron and N-acetyl-cysteine, failed to rescue the depleted cells from apoptosis (unpublished data)”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Discussion > How does glutamine depletion kill?
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In the paper
“oxaloacetate, which is a membrane-permeable Krebs cycle intermediate, or pyruvate, which can enter the cycle by converting into acetyl-CoA or oxaloacetate, completely prevented apoptosis in the absence of glutamine (Fig. 8, A and B).”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Results > Apoptosis caused by glutamine depletion is prevented by substrates of the Krebs cycle
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Oxaloacetate is a membrane-permeable Krebs cycle intermediate and pyruvate can enter the Krebs cycle by converting into acetyl-CoA or oxaloacetate.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“BSO failed to induce apoptosis in IER-MYC cells (Fig. 6 C), suggesting that glutathione deficiency alone could not be the cause of apoptosis induced by glutamine depletion.”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Results > Apoptosis is not caused by glutathione deficiency
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In the paper
“IER-MYC cells ceased to proliferate irrespective of ERTM-MYC activity if either any of the essential amino acids or glutamine were absent (unpublished data). Therefore, deregulation of cell cycle arrest by itself could not explain cell death caused by glutamine depletion.”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Results > A cell cycle arrest is not the cause of apoptosis
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In the paper
“omitting any of the essential amino acids from the tissue culture media failed to kill cells, at least over the time sufficient to kill by omitting glutamine (Fig. 4 B). Therefore, protein synthesis was not the cause of apoptosis induced by glutamine depletion.”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Results > A deficiency in protein synthesis or inhibition of mTOR did not cause apoptosis induced by glutamine depletion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Fig. S1 C demonstrates that the MYC moiety of ER-MYC makes cells sensitive to glutamine depletion”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Materials and methods > Online supplemental material
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- It may state two separate claims as one. 11
- Probably not a substantial claim. 15
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In the paper
“glutamine depletion not only failed to increase the p53 concentration, but even reversed the increase induced by activation of ERTM-MYC (Fig. 7).”
- Also stated in: § Glutamine depletion does not cause DNA damage · plain
“Phosphorylation of H2AX, as detected by immunofluorescence, was induced by etoposide and by activation of ERTM-MYC, but not by glutamine depletion (Fig. S2, available at http://www.jcb.org/cgi/content/full/jcb.200703099/DC1).”
- Also stated in: § Glutamine depletion does not cause DNA damage · hedged
“Hence, depletion of glutamine was unlikely to cause apoptosis by inducing DNA damage.”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Results > Glutamine depletion does not cause DNA damage
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Glutamine depletion does not cause DNA damage · plain
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In the paper
“the NADH/NAD ratio remained unchanged (Fig. 8 D) and lactate was still produced (Fig. S3, available at http://www.jcb.org/cgi/content/full/jcb.200703099/DC1) after glutamine depletion, even though at a lower rate, indicating that pyruvate was unlikely to rescue from glutamine depletion by being a substrate of LDH.”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Results > Apoptosis caused by glutamine depletion is prevented by substrates of the Krebs cycle
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In the paper
“rapamycin caused S6 dephosphorylation but had no effect on cell viability over the time sufficient to kill cells by glutamine depletion (Fig. 4 C). Hence, glutamine depletion caused apoptosis by affecting pathways that did not require mTOR activity.”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Results > A deficiency in protein synthesis or inhibition of mTOR did not cause apoptosis induced by glutamine depletion
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In the paper
“in our hands depletion of essential amino acids caused cell cycle arrest but not apoptosis”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Discussion > How does ectopic activity of MYC synergize with glutamine depletion to induce apoptosis?
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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In the paper
“Fig. S3 documents that lactate production remains largely unchanged after depletion of glutamine and is independent of ER-MYC activity”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Materials and methods > Online supplemental material
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“glutamine depletion caused cell cycle arrest irrespective of the ERTM-MYC activity (unpublished data)”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Discussion > How does ectopic activity of MYC synergize with glutamine depletion to induce apoptosis?
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“we used IER-MYC that expressed C9DN (IER-MYC–C9DN), which prevents cell disassembly but not the preceding steps of apoptosis (Fearnhead et al., 1998), thus avoiding artifacts associated with cell decomposition.”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Results > Apoptosis induced by glutamine depletion is not caused by ATP deficiency
What the sources say
- Not checked yetcites Fearnhead et al., 1998
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In the paper
“Identification was based on retention time and exact mass measurements after alignment of both axes with reference compounds, and confirmed by spiked standards.”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Materials and methods > CE-MS analysis
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In the paper
“metabolism of human cells is changed by oncogenes in various ways (Ramanathan et al., 2005)”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Results > Modification of nutrient requirements by acute activation of ectopically expressed MYC vary with cell type
What the sources say
- Not checked yetcites Ramanathan et al., 2005
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“previous reports suggested that depletion of glutamine kills because of stress caused by deficiency in proteins, ATP, glutathione, or nucleotides (for review see Ahluwalia et al., 1990; Fuchs and Bode, 2006).”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Results > Glutamine deprivation induces apoptosis selectively in cells with acutely activated ER-MYC
What the sources say
- Not checked yetcites Ahluwalia et al., 1990
- Not checked yetcites Fuchs and Bode, 2006
Tests✗ Asserted: fails✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. The authors may not put it forward as true.
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In the paper
“Adding OHT to the tissue culture medium caused translocation of ERTM-MYC to the nucleus (Fig. S1 A, available at http://www.jcb.org/cgi/content/full/jcb.200703099/DC1) and increased sensitivity of the cells to DNA damage (Fig. S1 B), which confirmed that the system functioned as expected (Eilers et al., 1989; Littlewood et al., 1995).”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Results
What the sources say
- Not checked yetcites Eilers et al., 1989
- Not checked yetcites Littlewood et al., 1995
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In the paper
“Pyruvate might affect cell viability by being a substrate of lactate dehydrogenase (LDH), which oxidizes NADH to NAD (Zielke et al., 1980).”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Results > Apoptosis caused by glutamine depletion is prevented by substrates of the Krebs cycle
What the sources say
- Not checked yetcites Zielke et al., 1980
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Treatments that induce glutamine deficiency or interfere with its metabolism as a substrate for nucleotide synthesis were highly successful in animals, but turned out to be unacceptably toxic in people and were largely abandoned (Ahluwalia et al., 1990).”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Discussion > Relevance of glutamine metabolism to cancer therapy
What the sources say
- Not checked yetcites Ahluwalia et al., 1990
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Overall, our study is consistent with the view that metabolic changes associated with carcinogenesis, and the energy metabolism in particular, might be much more complex than Warburg postulated”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Discussion > Relevance of glutamine metabolism to cancer therapy
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✗ Checkable: fails✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“our observations indicated that glutamine in our system is either the main source of Krebs cycle intermediates, as in some proliferating normal and cancer cells (Reitzer et al., 1979; Moreadith and Lehninger, 1984; Zielke et al., 1984; Kovacevic et al., 1991; Baggetto, 1992; Petch and Butler, 1994), or regulates the Krebs cycle activity.”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Discussion > How does glutamine depletion kill?
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In the paper
“suggests that the potential of glutamine metabolism as a target for cancer therapy may need revisiting”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Discussion > Relevance of glutamine metabolism to cancer therapy
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In the paper
“the NADH/NAD ratio determines rates of many processes, from glycolysis to histone modifications (for review see Ladurner, 2006)”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Results > Apoptosis caused by glutamine depletion is prevented by substrates of the Krebs cycle
What the sources say
- Not checked yetcites Ladurner, 2006
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“capillary electrophoresis coupled to mass spectrometry (CE-MS), an approach that estimates concentration of multiple metabolites in one sample (Soga et al., 2003).”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Results > Apoptosis caused by glutamine depletion is prevented by substrates of the Krebs cycle
What the sources say
- Not checked yetcites Soga et al., 2003
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In the paper
“All changes in brightness or contrast, if any done, were applied to the entire image.”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Materials and methods > Immunofluorescence
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In the paper
“To further decrease the chances of clonal selection, we used retroviral transduction rather than transient transfection to generate populations of normal human fibroblasts IMR90 that expressed ERTM-MYC (IER-MYC) or ERTM (IER); the latter served to exclude effects of OHT unrelated to MYC activity.”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Results
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“our results demonstrated that dependence of cells on glucose and the effects of its depletion vary among cell types and can depend on the combination of oncogenes expressed in these cells.”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“the Krebs cycle is not only a source of NADH for oxidative phosphorylation, but also a “hub” of numerous metabolic pathways (http://www.tcd.ie/Biochemistry/IUBMB-Nicholson/minimaps.html)”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Results > Apoptosis caused by glutamine depletion is prevented by substrates of the Krebs cycle
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our results suggest that the fate of normal human cells should be considered in evaluating nutrient deprivation as a strategy for cancer therapy”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Abstract
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None of the sources cited for this claim have been checked yet.
In the paper
“depletion of glucose induced apoptosis in rodent cells that were transduced with MYC, an oncogene that is abnormally expressed in many human cancers (Nesbit et al., 1999), but not in the parental cell line (Shim et al., 1998).”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Introduction
What the sources say
- Not checked yetcites Shim et al., 1998
- Not checked yetcites Nesbit et al., 1999
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Fig. S1, A and B document that ER-MYC is activated as expected”
§ Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells > Materials and methods > Online supplemental material
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The paper relies on this without support.
Metabolism can vary among species.
“Considering that metabolism can vary among species, and that human rather than animal tumors are of primary interest, we used human cells.”
The paper relies on this without support.
Glutamine is made by cells, making the requirement for exogenous glutamine appear unnecessary.
“However, glutamine is made by cells, which makes the requirement for exogenous glutamine appear unnecessary.”
The paper relies on this without support.
Oxaloacetate is a membrane-permeable Krebs cycle intermediate and pyruvate can enter the Krebs cycle by converting into acetyl-CoA or oxaloacetate.
“oxaloacetate, which is a membrane-permeable Krebs cycle intermediate, or pyruvate, which can enter the cycle by converting into acetyl-CoA or oxaloacetate, completely prevented apoptosis in the absence of glutamine (Fig. 8, A and B).”
The paper relies on this without support.
Why glutamine is required for cell viability is not entirely clear.
“Surprisingly, why glutamine is required for cell viability, or, in other words, why depletion of glutamine would kill cells, is not entirely clear.”
The paper relies on this without support.
p53 is mutated in many cancers.
“which is an advantage as this protein is mutated in many cancers”
Claims other papers make about this one
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The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Furthermore, depending on the tissue of origin, cancer cells use various routes of glutamine metabolism. Some have been shown to require an exogenous glutamine supply for malignant proliferation [71,72], whereas others do not [73] and can synthesize it de novo [74].”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [71]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Cancer cells often consume glutamine, and those dependent on Myc signaling are highly sensitive to glutamine withdrawal (Yuneva et al., 2007).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Yuneva et al., 2007
Experimental — accuracy not yet measuredIn the citing paper
“Similarly, checkpoint kinase 1 (CHK1) inhibitors625–627 and glutaminase (GLS) inhibitors628–634 are also considered potential candidates for treating Myc-overexpressing cancers.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [628]
In the citing paper
“Providing cells with αKG, oxaloacetate, or pyruvate is sufficient to rescue cancer cell proliferation in conditions of glutamine starvation, confirming that glutamine supports proliferation by replenishing depleted TCA cycle intermediates, a process termed anaplerosis (Altman et al., 2016; Weinberg et al., 2010; Yuneva et al., 2007).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Yuneva et al., 2007
In the citing paper
“In certain contexts, MYC-transformed cancers become glutamine dependent and undergo apoptosis in the absence of glutamine (Yuneva et al., 2007).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Yuneva et al., 2007
In the citing paper
“In c-myc-transformed cells in particular, glutamine deprivation leads to the collapse of the TCA cycle and triggers cell death, which can be rescued by the addition of oxaloacetate or a membrane-permeable form of α-ketoglutarate (Wise et al., 2008; Yuneva et al., 2007).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Yuneva et al., 2007
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
MYC-associated DNA damage is both reported and denied
MajorThe Discussion says no increase in DNA damage was detected after ERTM-MYC activation, but the Results say ERTM-MYC activation induced phosphorylation of H2AX, which the paper uses as a DNA-damage reporter.
“However, we detected no increase in the concentration of ROS or DNA damage either after activation of ERTM-MYC or depleting glutathione.”
“Phosphorylation of H2AX, as detected by immunofluorescence, was induced by etoposide and by activation of ERTM-MYC, but not by glutamine depletion (Fig. S2, available at http://www.jcb.org/cgi/content/full/jcb.200703099/DC1).”
CrmA result cites a nonexistent Figure 3 panel
MinorThe text cites Figure 3 D for the CrmA result, but the Figure 3 caption identifies the CrmA experiment as panel C and lists no panel D.
“whereas crmA, a viral inhibitor of the extrinsic pathway (Enari et al., 1995), had no effect (Fig. 3 D).”
“(C) IER-MYC transduced with CrmA or vector alone were treated as in A except anti-Fas (α-CD95) antibody was added as indicated.”
Figure 6 C refers to a schematic as its treatment protocol
MinorThe caption says the cells in panel C were treated as in panel A, but panel A is a biosynthesis diagram. The treatment conditions are described in panel B.
“(C) IER-MYC cells were treated as in A except the cells were collected at 24 h of incubation in the indicated media to determine the rate of apoptosis.”
“(A) Biosynthesis of glutathione. (B) IER-MYC–C9DN were incubated with OHT (MYCON) or ethanol (MYCOFF) for 24 h, and then transferred to the medium depleted of glutamine or supplemented with 100 μM BSO.”
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Metadata
- Authors
- Yuneva, M., Zamboni, N., Oefner, P., Sachidanandam, R., & Lazebnik, Y.
- Affiliations
- University of California, San Francisco (US)
- ETH Zurich (CH)
- University of Regensburg (DE)
- Cold Spring Harbor Laboratory (US)
- Corresponding author
- Lazebnik, Yuri
- Venue
- The Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2007-07-02
- Volume
- 178
- Issue
- 1
- Pages
- 93-105
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC2064426
- OpenAlex
- W2112861594
- Cited by
- 690
- References
- 72
- Citations by year
- 2026: 16 · 2025: 27 · 2024: 26 · 2023: 46 · 2022: 36 · 2021: 36 · 2020: 32 · 2019: 40 · 2018: 39 · 2017: 56 · 2016: 49 · 2015: 47 · 2014: 50 · 2013: 46 · 2012: 42
- FWCI
- 7.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Cell Biology (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- National Cancer Institute (CA-13106-31, P01CA013106)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- glutamine deprivation, glucose deprivation, c-Myc, apoptosis, Krebs cycle intermediates, nutrient deprivation, cancer therapy, glutamine metabolism, cell viability, glucose metabolism
- MeSH terms
- Proto-Oncogene Mas, Cell Line, Cells, Cultured, Fibroblasts, Gene Expression Regulation, Glucose, Glutamine, Humans, Lung, Male, Retroviridae, Skin, Transduction, Genetic, Proto-Oncogene Proteins c-myc, Apoptosis, Cell Culture Techniques
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