Glycolytic Enzymes Can Modulate Cellular Life Span
Open accessPublished version of a preprint
Abstract
An unbiased screen for genes that can immortalize mouse embryonic fibroblasts identified the glycolytic enzyme phosphoglycerate mutase (PGM). A 2-fold increase in PGM activity enhances glycolytic flux, allows indefinite proliferation, and renders cells resistant to ras-induced arrest. Glucosephosphate isomerase, another glycolytic enzyme, displays similar activity and, conversely, depletion of PGM or glucosephosphate isomerase with short interfering RNA triggers premature senescence. Immortalized mouse embryonic fibroblasts and mouse embryonic stem cells display higher glycolytic flux and more resistance to oxidative damage than senescent cells. Because wild-type p53 down-regulates PGM, mutation of p53 can facilitate immortalization via effects on PGM levels and glycolysis.
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- Findingnone given
A 2-fold increase in PGM activity enhances glycolytic flux.
“A 2-fold increase in PGM activity enhances glycolytic flux, allows indefinite proliferation, and renders cells resistant to ras-induced arrest.”
Quote in the paperSubstantial claim- Rests on an assumption: PGM catalyses the transfer of phosphate from 3-phosphoglycerate to 2-phosphoglycerate.
- Findingown data
Ectopic GPI showed a similar effect on cell proliferation as PGM-M.
“Ectopic GPI showed a similar effect on cell proliferation as PGM-M (Fig. 3A)”
Quote in the paperSubstantial claim - Findingown data
A retrovirus encoding PGM-M conferred unlimited proliferation on primary MEFs with an efficiency comparable to that of p53DN.
“a retrovirus encoding PGM-M conferred unlimited proliferation on primary MEFs with an efficiency comparable to that of p53DN.”
Quote in the paperSubstantial claim- Rests on an assumption: Primary mouse embryo fibroblasts lose proliferative capacity after only 10 to 20 population doublings despite having exceptionally long telomeres.
- Findingreasoning
Immortalized mouse embryonic fibroblasts and mouse embryonic stem cells display more resistance to oxidative damage than senescent cells.
“Immortalized mouse embryonic fibroblasts and mouse embryonic stem cells display higher glycolytic flux and more resistance to oxidative damage than senescent cells.”
Quote in the paperSubstantial claim - Findingown data
PGM-M can immortalize MEFs from C57BL6 mice.
“We also confirmed that PGM-M can immortalize MEFs from C57BL6 mice, excluding some genetic predisposition in the CD1 strain (data not shown).”
Quote in the paperSubstantial claim
- Findingown data
A 2-fold increase in PGM activity allows indefinite proliferation.
“A 2-fold increase in PGM activity enhances glycolytic flux, allows indefinite proliferation, and renders cells resistant to ras-induced arrest.”
Quote in the paperSubstantial claim- Rests on an assumption: Primary mouse embryo fibroblasts lose proliferative capacity after only 10 to 20 population doublings despite having exceptionally long telomeres.
- Findingown data
All mutations (R90Q, R116Q, R117Q) ablate or substantially reduce the enhancement of PGM activity conferred by wild-type PGM-M.
“All of the mutations were shown to ablate or substantially reduce the enhancement of PGM activity conferred by wild-type PGM-M (Fig. 2C).”
Quote in the paperSubstantial claim - Findingown data
PGM-B is much more abundant than PGM-M in cultured MEFs.
“Northern blotting using cDNA probes for the two mouse isoforms indicated that PGM-B is much more abundant than PGM-M in cultured MEFs (Fig. 2B).”
Quote in the paperNot a substantial claim - Findingown data
A 2-fold increase in PGM activity renders cells resistant to ras-induced arrest.
“A 2-fold increase in PGM activity enhances glycolytic flux, allows indefinite proliferation, and renders cells resistant to ras-induced arrest.”
Quote in the paperSubstantial claim - Findingnone given
Immortalized mouse embryonic fibroblasts and mouse embryonic stem cells display higher glycolytic flux than senescent cells.
“Immortalized mouse embryonic fibroblasts and mouse embryonic stem cells display higher glycolytic flux and more resistance to oxidative damage than senescent cells.”
Quote in the paperSubstantial claim - Findingown data
An unbiased screen for genes that can immortalize mouse embryonic fibroblasts identified the glycolytic enzyme phosphoglycerate mutase (PGM).
“An unbiased screen for genes that can immortalize mouse embryonic fibroblasts identified the glycolytic enzyme phosphoglycerate mutase (PGM).”
Quote in the paperSubstantial claim- Rests on an assumption: Primary mouse embryo fibroblasts lose proliferative capacity after only 10 to 20 population doublings despite having exceptionally long telomeres.
- Findingown data
Depletion of PGM or GPI with short interfering RNA triggers premature senescence.
“depletion of PGM or glucosephosphate isomerase with short interfering RNA triggers premature senescence”
Quote in the paperSubstantial claim - Findingown data
PGM- and p53DN-immortalized MEFs underwent a senescence-like arrest upon ectopic expression of p16 Ink4a or p19 Arf.
“Both PGM-and p53DNimmortalized MEFs underwent a senescence-like arrest upon ectopic expression of p16 Ink4a or p19 Arf , implying that they had not sustained mutations in the effector pathways required for senescence (data not shown).”
Quote in the paperSubstantial claim - Findingown data
Glucosephosphate isomerase (GPI) displays similar activity to PGM in immortalizing MEFs.
“Glucosephosphate isomerase, another glycolytic enzyme, displays similar activity”
Quote in the paperSubstantial claim - Findingown data
In MEFs infected with retroviruses encoding either PGM isoform, total PGM activity was increased approximately 2-fold relative to endogenous levels in uninfected cells.
“In MEFs infected with retroviruses encoding either PGM isoform, the total PGM activity was increased approxi-mately 2-fold relative to the endogenous levels in uninfected cells (Fig. 2C and data not shown).”
Quote in the paperSubstantial claim- Rests on an assumption: PGM catalyses the transfer of phosphate from 3-phosphoglycerate to 2-phosphoglycerate.
- Findingown data
R116Q and R117Q mutations seemed to promote rather than alleviate senescence, as compared to MEFs infected with the empty vector control.
“Interestingly, the R116Q and R117Q mutations seemed to promote rather than alleviate senescence, as compared to MEFs infected with the empty vector control (Fig. 2D and data not shown).”
Quote in the paperNot a substantial claim - Findingown data
PGM-M-expressing MEFs did not acquire the ability to form colonies in soft agar.
“the PGM-M-expressing MEFs did not acquire the ability to form colonies in soft agar, and are thus not fully transformed (Fig. 1D).”
Quote in the paperSubstantial claim - Findingown data
Oncogenic ras causes lower DCF staining in PGM-M MEFs than in wild-type MEFs.
“We found that oncogenic ras induced less DCF staining in PGM-M MEFs compared with wild-type MEFs (Fig. 6C), in line with our findings that PGM-immortalized MEFs are resistant to arrest by oncogenic ras (Fig. 1C).”
Quote in the paperSubstantial claim - Findingown data
No evidence was found for transcriptional regulation of PGM-M or PGM-B in MEFs.
“In cardiac myocytes, PGM-M is a direct transcriptional target of p53 (41), but we did not find evidence for transcriptional control of PGM-M or PGM-B in MEFs (Fig. 2B and data not shown).”
Quote in the paperNot a substantial claim - Findingown data
Cotransfection of p53-/- MEFs with PGM-GFP and increasing amounts of p53 caused a marked and dose-dependent reduction in the level of PGM-GFP.
“we observed a marked and dose-dependent reduction in the level of PGM-GFP (Fig. 5C) consistent with reduced translation or stability.”
Quote in the paperSubstantial claim - Findingown data
In passage 8 MEFs, ectopic expression of GPI or PGM-M increased the rate of glucose detritiation approximately 2-fold compared with control cells infected with the empty vector.
“In passage 8 MEFs, ectopic expression of GPI or PGM-M increased the rate of glucose detritiation approximately 2-fold compared with control cells infected with the empty vector (Fig. 3B, filled bar).”
Quote in the paperSubstantial claim - Findingown data
An analogous effect was noted on the ratio of lactate production to glucose consumption.
“An analogous effect was noted on the ratio of lactate production to glucose consumption (Fig. 3B, open bar), suggesting that these enzymes were indeed capable of stimulating glycolytic flux.”
Quote in the paperSubstantial claim - Findingown data
CGR8 mouse embryonic stem cells are remarkably resistant to oxidative stress, with only marginal viability effects at hydrogen peroxide concentrations up to 100 μmol/L.
“CGR8 cells proved to be remarkably resistant to oxidative stress, showing only marginal effects on viability at hydrogen peroxide concentrations as high as 100 Amol/L (Fig. 6A).”
Quote in the paperSubstantial claim - Findingnone given
Embryonic stem cells also display an elevated lactate/glucose ratio.
“Embryonic stem cells also display an elevated lactate/glucose ratio.”
Quote in the paperNot a substantial claim - Findingown data
Inhibition of PGM or GPI triggers premature senescence.
“Furthermore, inhibition of either of these two enzymes triggers premature senescence.”
Quote in the paperSubstantial claim - Findingown data
A possible association exists between PGM protein levels and p53 function.
“We did find a potential link between PGM protein level and p53 function (Fig. 5).”
Quote in the paperNot a substantial claim - Findingown data
In nine separate 3T3 MEF cultures allowed to undergo spontaneous immortalization, PGM activity was invariably elevated relative to the senescent population.
“In nine separate 3T3 MEF cultures allowed to undergo spontaneous immortalization, PGM activity was invariably elevated relative to the senescent population (data not shown).”
Quote in the paperSubstantial claim - Findingown data
MEFs expressing PGM-M or p53DN are significantly more resistant to hydrogen peroxide than empty vector controls.
“MEFs expressing PGM-M or p53DN were significantly more resistant to hydrogen peroxide than the controls infected with the empty vector (Fig. 6A).”
Quote in the paperSubstantial claim - Findingown data
Vector control cells exhibit roughly a twofold rise in 8-OHdG from passage 8 to passage 12.
“The vector control cells showed an f2-fold increase in 8-OHdG levels between passage 8 and passage 12, consistent with the accumulation of oxidative DNA damage as cells approach senescence (Fig. 6D).”
Quote in the paperNot a substantial claim - Findingown data
siRNA against PGM or GPI inhibited proliferation of early-passage MEFs.
“the siRNA against either PGM or GPI inhibited proliferation (Supplemental Fig. A)”
Quote in the paperSubstantial claim - Findingcitation
Tetracycline-regulated expression of wild-type p53 (GFP tagged) in the TGP53-4 mouse cell line caused a significant decline in endogenous PGM activity.
“tetracycline regulated expression of wild-type p53 (GFP tagged) in the TGP53-4 mouse cell line (27) caused a significant decline in endogenous PGM activity (Fig. 5B).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [27] source
Not checked in the free run.
- Findingown data
Glycolytic activity is reestablished during spontaneous immortalization of MEFs.
“Here we have established that early-passage MEFs have high glycolytic activity, which declines during replicative senescence and is reestablished during spontaneous immortalization.”
Quote in the paperSubstantial claim - Findingown data
The other glycolytic enzymes tested had little if any effect on population doublings and senescent-associated h-galactosidase staining.
“The other glycolytic enzymes tested had little if any effect, as judged by population doublings and senescentassociated h-galactosidase staining (Fig. 3A and data not shown).”
Quote in the paperSubstantial claim - Findingown data
siRNA against PGM or GPI induced premature senescence as assessed by senescent-associated h-galactosidase activity.
“induced premature senescence as assessed by senescent-associated h-galactosidase activity (Fig. 3D).”
Quote in the paperSubstantial claim - Findingown data
Early-passage MEFs have high glycolytic activity.
“Here we have established that early-passage MEFs have high glycolytic activity, which declines during replicative senescence and is reestablished during spontaneous immortalization.”
Quote in the paperSubstantial claim - Findingown data
This increase in PGM activity was accompanied by similar increases in glucose detritiation and lactate production.
“This was accompanied by similar increases in glucose detritiation and lactate production.”
Quote in the paperSubstantial claim - Findingown data
Mouse embryonic stem cells show naturally elevated PGM activity and glycolysis even when cultured at ambient 20% O2.
“Most interestingly, mouse embryonic stem cells, which do not senesce in vitro, display naturally high levels of PGM activity and glycolysis even at ambient 20% O 2 (see below).”
Quote in the paperNot a substantial claim- Rests on an assumption: Mouse embryonic stem cells do not senesce in vitro.
- Findingown data
Glycolytic flux declined as the culture senesced and then rose again coincident with spontaneous immortalization.
“glycolytic flux, as measured by glucose detritiation, declined as the culture senesced and then rose again coincident with spontaneous immortalization (Fig. 4A, top).”
Quote in the paperSubstantial claim - Findingown data
MEFs expressing p53DN showed a relatively modest but significant increase in PGM activity compared with vector-only controls.
“MEFs expressing p53DN showed a relatively modest but significant increase in PGM activity compared with vector-only controls (Fig. 5A).”
Quote in the paperSubstantial claim - Findingown data
PGK reproducibly showed an intermediate effect with sustained cell proliferation but at a reduced rate compared with PGM-M.
“PGK reproducibly showed an intermediate effect with sustained cell proliferation but at a reduced rate compared with PGM-M.”
Quote in the paperSubstantial claim - Findingown data
Glycolytic activity declines during replicative senescence in MEFs.
“Here we have established that early-passage MEFs have high glycolytic activity, which declines during replicative senescence and is reestablished during spontaneous immortalization.”
Quote in the paperSubstantial claim - Findingcitation
p53DN-expressing cells show reduced DCF staining.
“As previously reported (18), the p53DN-expressing cells showed reduced DCF staining (Fig. 6B).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [18] source
Not checked in the free run.
- Findingown data
Ectopic expression of PGM-GFP in wild-type MEFs resulted in the appearance of a higher molecular weight form of the protein.
“ectopic expression of PGM-GFP in wild-type MEFs resulted in the appearance of a higher molecular weight form of the protein (Fig. 5D, asterisk).”
Quote in the paperNot a substantial claim - Findingown data
MEFs show severe loss of viability even at low hydrogen peroxide concentrations.
“In comparison, MEFs showed severe loss of viability even at low concentrations of hydrogen peroxide.”
Quote in the paperSubstantial claim - Findingown data
PGM-M- or GPI-expressing MEFs show markedly lower DCF staining than vector controls at passages 8 and 12.
“The PGM-M-or GPI-expressing MEFs also had significantly less DCF staining than vector control cells at passage 8 and passage 12 (Fig. 6B; Supplemental Fig. D and data not shown).”
Quote in the paperSubstantial claim - Findingown data
No change in PGM mRNA levels was observed following introduction of p53DN or wild-type p53.
“we did not observe a change in PGM mRNA levels following the introduction of p53DN (Fig. 2) or wild-type p53 (data not shown).”
Quote in the paperSubstantial claim - Findingown data
The higher molecular weight form of PGM-GFP was detectable by immunoblotting with an antibody against ubiquitin after immunoprecipitation via the GFP epitope.
“When immunoprecipitated via the GFP epitope, the higher molecular weight form was detectable by immunoblotting with an antibody against ubiquitin (Fig. 5D).”
Quote in the paperSubstantial claim - Findingown data
PGM levels were unaffected by either Mdm2 or p53RFP.
“However, PGM levels were unaffected by either Mdm2 or p53RFP, two ubiquitin ligases that are known to be regulated by p53 (refs. 35, 36; data not shown).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Findingown data
Total PGM activity increased approximately 2-fold in the immortal segregants.
“Total PGM activity increased approximately 2-fold in the immortal segregants, analogous to the increase observed upon ectopic expression of PGM-M in Fig. 2C”
Quote in the paperSubstantial claim - Findingown data
Mammalian cells' glycolytic flux can be genetically altered with surprising ease, at least in MEFs.
“Although it has been suggested that the activity of complex metabolic pathways cannot be modulated by the abundance of a single component enzyme (49), our studies reveal the unexpected ease with which the glycolytic flux of mammalian cells can be genetically manipulated, at least in MEFs.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [49] source
Not checked in the free run.
- Interpretationown data
PGM-M-expressing MEFs are not fully transformed.
“the PGM-M-expressing MEFs did not acquire the ability to form colonies in soft agar, and are thus not fully transformed (Fig. 1D).”
Quote in the paperSubstantial claim - Interpretationreasoning
Total PGM activity is important for immortalization, rather than a specific attribute of the PGM-M isoform.
“These results imply that the total PGM activity is important for immortalization, rather than a specific attribute of the PGM-M isoform.”
Quote in the paperSubstantial claim - Interpretationown data
PGM- and p53DN-immortalized MEFs had not sustained mutations in the effector pathways required for senescence.
“Both PGM-and p53DNimmortalized MEFs underwent a senescence-like arrest upon ectopic expression of p16 Ink4a or p19 Arf , implying that they had not sustained mutations in the effector pathways required for senescence (data not shown).”
Quote in the paperNot a substantial claim - Premisecitation
The life span of mouse and human fibroblasts can be extended by culturing them under low-oxygen conditions.
“the life span of mouse and human fibroblasts can be extended by culturing them under low-oxygen conditions (12,13).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationown data
Wild-type p53 downregulates PGM.
“Because wild-type p53 downregulates PGM, mutation of p53 can facilitate immortalization via effects on PGM levels and glycolysis.”
- Also stated in: § Immortalization Correlates with Effects on Glycolysis. · hedged
“These results suggest that p53 is able to down-regulate PGM”
Quote in the paperSubstantial claim - Also stated in: § Immortalization Correlates with Effects on Glycolysis. · hedged
- Interpretationown data
PGM-M immortalization of MEFs is a single genetic event.
“This confirms that PGM-M immortalization of MEFs is a single genetic event.”
Quote in the paperSubstantial claim - Premisecitation
Telomere-independent mechanisms are important in senescence.
“However, it is clear that telomere-independent mechanisms are also important (10).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] source
Not checked in the free run.
- Interpretationown data
PGM activity is required for immortalization of MEFs.
“Thus, we concluded that PGM activity is required for immortalization of MEFs.”
Quote in the paperSubstantial claim - Interpretationown data
PGM-induced immortalization is not equivalent to that conferred by loss of p53.
“These data suggest that PGM-induced immortalization is not equivalent to that conferred by loss of p53.”
Quote in the paperSubstantial claim - Interpretationreasoning
Mutation of p53 can facilitate immortalization via effects on PGM levels and glycolysis.
“Because wild-type p53 downregulates PGM, mutation of p53 can facilitate immortalization via effects on PGM levels and glycolysis.”
Quote in the paperSubstantial claim - Interpretationown data
Modulation of some but not all glycolytic enzymes can influence cell proliferation via effects on glycolysis.
“These observations are in line with the idea that modulation of some but not all glycolytic enzymes can influence cell proliferation via effects on glycolysis.”
Quote in the paperSubstantial claim - Interpretationreasoning
Mouse embryonic stem cells display the Warburg effect.
“Thus, they display the Warburg effect.”
Quote in the paperNot a substantial claim- Rests on an assumption: Mouse embryonic stem cells do not senesce in vitro.
- Interpretationown data
There is a correlation between the ability of glycolytic enzymes to enhance glycolysis and their ability to bypass senescence in MEFs.
“The results imply a correlation between the ability of glycolytic enzymes to enhance glycolysis and their ability to bypass senescence in MEFs.”
Quote in the paperSubstantial claim - Interpretationreasoning
Glycolytic activation might shield against oxidative damage from reactive oxygen species generated by mitogenic stimulation in vivo.
“Glycolytic activation may therefore protect against oxidative damage caused by reactive oxygen species production of mitogenic bombardment in vivo.”
Quote in the paperSubstantial claim - Premisecitation
Reduced-oxygen culture conditions can delay cellular senescence.
“Growing cells under reduced-oxygen conditions can delay senescence and it has recently been reported that MEFs are essentially immortal and show less oxidative DNA damage if propagated in 3% oxygen (13).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] source
Not checked in the free run.
- Interpretationown data
The Warburg effect may reflect a mechanism for escaping the restrictions to cellular life span caused by oxidative stress.
“Our findings suggest that the Warburg effect may reflect a mechanism for escaping the restrictions to cellular life span caused by oxidative stress.”
Quote in the paperSubstantial claim- Rests on an assumption: Primary mouse embryo fibroblasts lose proliferative capacity after only 10 to 20 population doublings despite having exceptionally long telomeres.
- Rests on an assumption: Mouse cells are particularly sensitive to oxidative stress but also escape from the ensuing growth arrest at a relatively high frequency.
- Interpretationreasoning
Glycolytic activation protects from oxidative damage.
“Glycolytic activation protects from oxidative damage, and we hypothesize that the constitutively active glycolytic pathway observed in embryonic stem cells at atmospheric O 2 conditions contributes to their immortal characteristics even though they present a robust p53 response to DNA damage (44,45).”
Quote in the paperSubstantial claim- Rests on an assumption: In standard 20% oxygen tissue culture, oxidative stress strongly affects cellular life span.
- Interpretationown data
p53 is able to down-regulate PGM.
“These results suggest that p53 is able to down-regulate PGM”
Quote in the paperSubstantial claim - Interpretationown data
The rise in 8-OHdG in vector control cells agrees with oxidative DNA damage building up as cells near senescence.
“The vector control cells showed an f2-fold increase in 8-OHdG levels between passage 8 and passage 12, consistent with the accumulation of oxidative DNA damage as cells approach senescence (Fig. 6D).”
Quote in the paperNot a substantial claim - Interpretationown data
Expression of PGM or GPI can lower reactive oxygen species production in cells over serial culture.
“These results indicate that PGM or GPI expression can reduce reactive oxygen species production in the cells during serial culture.”
Quote in the paperSubstantial claim - Premisecitation
In an analysis of 15 glucose transporter and glycolytic genes in embryonic stem cells lacking HIF1a, only PGM and GPI were exceptions.
“Interestingly, PGM and GPI were the only exceptions noted in a study of 15 glucose transporter and glycolytic genes in HIF1a null embryonic stem cells (40).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [40] source
Not checked in the free run.
- Interpretationown data
The reduction in PGM-GFP level is consistent with reduced translation or stability.
“we observed a marked and dose-dependent reduction in the level of PGM-GFP (Fig. 5C) consistent with reduced translation or stability.”
Quote in the paperSubstantial claim - Interpretationown data
p53's role in senescence cannot be attributed only to its effects on PGM down-regulation, since PGM fails to overcome cell cycle arrest caused by ectopic p53.
“However, as PGM cannot overcome a cell cycle arrest induced by ectopic p53 (data not shown), the role of p53 in senescence cannot be explained solely by effects on PGM down-regulation.”
Quote in the paperSubstantial claim - Interpretationown data
Under normal oxygen culture, PGM or GPI may shield cells from senescence caused by oxidative damage.
“Taken together, these data are consistent with the notion that PGM or GPI can protect cells from the senescence effect of oxidative damage under normal oxygen culture conditions.”
Quote in the paperSubstantial claim- Rests on an assumption: In standard 20% oxygen tissue culture, oxidative stress strongly affects cellular life span.
- Premisecitation
Switching cells from 3% to 20% O2 conditions can promote senescence.
“Switching cells from 3% to 20% O 2 conditions can promote senescence (13), and in human fibroblasts senescence can be mimicked experimentally by exposing cells to low doses of hydrogen peroxide (14,43).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] source
Not checked in the free run.
- Interpretationreasoning
Thus, a tumor may withstand damaging free radical production.
“In effect, the tumor can resist damaging free radical production.”
Quote in the paperSubstantial claim - Premisecitation
Human thymocytes show a well-established link among glycolysis, reactive oxygen species, and cell proliferation.
“A correlation between glycolysis, reactive oxygen species, and cell proliferation has been clearly established in human thymocytes (42).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [42] source
Not checked in the free run.
- Interpretationreasoning
For small or well-vascularized tumors, glycolytic activation might be an early and crucial step in tumorigenesis.
“Thus, in a small or well-vascularized tumor, glycolytic activation may be an early and essential step in tumorigenesis.”
Quote in the paperSubstantial claim - Premisecitation
Human fibroblast senescence can be experimentally reproduced by treating cells with low doses of hydrogen peroxide.
“Switching cells from 3% to 20% O 2 conditions can promote senescence (13), and in human fibroblasts senescence can be mimicked experimentally by exposing cells to low doses of hydrogen peroxide (14,43).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationreasoning
If a tumor later becomes anoxic by outgrowing its blood supply, active glycolysis is presumably still beneficial.
“A tumor that subsequently becomes anoxic by outgrowing its vasculature is also presumably well served by active glycolysis.”
Quote in the paperNot a substantial claim - Interpretationown data
Modulating glycolysis genetically or pharmacologically could also influence animal life span.
“Genetic or pharmaceutical modulation of the glycolytic pathway might also have an effect on animal life span, as our data support the rate-of-living oxygen radical theory of cellular and organismal aging (50).”
Quote in the paperSubstantial claim - Interpretationown data
The study's findings lend support to the rate-of-living oxygen radical theory of aging in cells and organisms.
“Genetic or pharmaceutical modulation of the glycolytic pathway might also have an effect on animal life span, as our data support the rate-of-living oxygen radical theory of cellular and organismal aging (50).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [50] source
Not checked in the free run.
- Premisecitation
Regardless of anoxia, tumors are probably highly dependent on glycolysis.
“Because tumors, whether anoxic or not, are likely to be highly glycolytically dependent (48), it may be worth exploring antiglycolytic agents that do not cross the blood-brain barrier as potential cancer therapeutics.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [48] source
Not checked in the free run.
- May combine two claims. 16
- Classified as probably not a substantial claim. 14
May combine two claims.
Findingown dataPGM-B was also able to immortalize MEFs, although the cells showed consistently slower growth rates than parallel cultures expressing either PGM-M or p53DN.
“Importantly, PGM-B was also able to immortalize MEFs, although the cells showed consistently slower growth rates than parallel cultures expressing either PGM-M or p53DN (data not shown).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
FindingcitationOncogenic ras caused neoplastic transformation of p53DN-expressing cells.
“whereas oncogenic ras caused neoplastic transformation of the p53DN-expressing cells, as expected (22,29,30)”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
Findingown dataSuperinfection with Cre recombinase reversed the senescence bypass in cells immortalized by PGM-M or p53DN, but had no effect on spontaneously immortalized MEFs (3T3 cells) infected with empty vector.
“Superinfection with a retrovirus encoding Cre recombinase, which will excise the integrated proviral DNA, reversed the senescence bypass in cells immortalized by PGM-M or p53DN, but had no effect on spontaneously immortalized MEFs (3T3 cells) infected with the empty pHygroMarx II vector (Fig. 1B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMEFs transduced with ectopic PGM-M showed relatively physiologic levels of expression, but MEFs immortalized by p53DN showed no significant up-regulation of PGM-M or PGM-B mRNA.
“MEFs transduced with ectopic PGM-M showed relatively physiologic levels of expression, but MEFs immortalized by p53DN showed no significant up-regulation of PGM-M or PGM-B mRNA (Fig. 2B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataWild-type MEFs rapidly arrested upon infection with ras-Val12, whereas MEFs expressing either PGM-M or p53DN continued to proliferate vigorously in the presence of ras-Val12.
“Wild-type MEFs (at passage 6) rapidly arrested upon infection with a retrovirus encoding ras-Val12, whereas MEFs expressing either PGM-M or p53DN (at passage 8) continued to proliferate vigorously in the presence of ras-Val12 (Fig. 1C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIntroduction of PGM or GPI does not prevent accumulation of 8-OHdG but reduces levels by about 2-fold at each passage.
“Introduction of PGM or GPI did not prevent the accumulation of 8-OHdG but reduced the levels by about 2-fold at each passage.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown datasiRNA against GAPDH had no effect on cell behavior despite reducing the activity of the enzyme.
“In contrast, the siRNA against GAPDH had no effect on cell behavior despite reducing the activity of the enzyme.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown datasiRNA against PGM or GPI reduced cellular ATP content by 34% and 19%, respectively.
“reduced the cellular ATP content by 34% and 19%, respectively (data not shown)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPhosphofructokinase and enolase had no impact on glucose detritiation or lactate/glucose ratio.
“In contrast, phosphofructokinase and enolase had no impact on these parameters.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCGR8 mouse embryonic stem cells showed enhanced glycolytic flux and concomitant elevation in total PGM activity relative to early-passage MEFs.
“CGR8 cells showed enhanced glycolytic flux and concomitant elevation in total PGM activity relative to earlypassage MEFs.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCancer cells maintain high rates of aerobic glycolysis under high-oxygen conditions, known as the Warburg effect.
“Cancer cells are able to maintain high rates of aerobic glycolysis even under the high-oxygen (20%) conditions of normal tissue culture.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [1] source
Not checked in the free run.
- cites [2]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationEnhanced glycolysis is a distinctive marker of cancer progression.
“several recent studies have shown that enhanced glycolysis is a distinctive marker of cancer progression (4,5)”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [4] source
Not checked in the free run.
- cites [5]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDamaged telomeres trigger a p53-mediated cell cycle arrest.
“Damaged telomeres eventually register as a form of DNA damage (8) triggering among other things a p53-mediated cell cycle arrest (9).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationProduction of reactive oxygen species underlies the premature senescence phenotype induced by oncogenes such as ras.
“the production of reactive oxygen species seems to underlie the premature senescence phenotype induced by oncogenes such as ras (15).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15] source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationNormal somatic cells achieve a limited number of population doublings before entering replicative senescence under standard tissue culture conditions.
“Under standard conditions of tissue culture, normal somatic cells achieve a limited number of population doublings before entering a growth-arrested state known as replicative senescence (6,7).”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAlmost all immortal cell clones that emerge have defects in either p53 or one of its upstream regulators or downstream effectors.
“Almost all of the immortal cell clones that emerge have defects in either p53 or one of its upstream regulators or downstream effectors (16,17)”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDeliberate oxidative stress can elicit a senescence-like arrest.
“deliberate oxidative stress, for example, with low doses of hydrogen peroxide, can elicit a senescence-like arrest (14)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [14] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThere is a correlation between expression of oncogenes such as ras, myc, or src and enhanced aerobic glycolysis.
“a correlation has been noted between the expression of oncogenes such as ras, myc, or src and enhanced aerobic glycolysis (1).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation8-OHdG is among the most common DNA lesions resulting from oxidative damage.
“To directly assess whether these effects could protect the cells from oxidative damage, we compared the levels of 8-OHdG, which is one of the most abundant types of DNA lesions caused by oxidative damage (37), in the genomic DNA by HPLC (Fig. 6D).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationOncogenic ras can stimulate reactive oxygen species production.
“Because oncogenic ras can also stimulate reactive oxygen species production (15), we examined the effect of oncogenic ras on reactive oxygen species production in PGM or wild-type MEFs.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCardiac myocytes have PGM-M as a direct transcriptional target of p53.
“In cardiac myocytes, PGM-M is a direct transcriptional target of p53 (41), but we did not find evidence for transcriptional control of PGM-M or PGM-B in MEFs (Fig. 2B and data not shown).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [41]
Not checked in the free run.
May combine two claims.
Interpretationown dataThe pattern of glycolytic activity changes is more than correlative, as shown by finding PGM-M in a genetic screen and by the ability of a twofold rise in enzyme activity to reversibly immortalize MEFs.
“That this pattern is more than correlative is evidenced by the identification of PGM-M in a genetic screen for cDNAs that overcome senescence and the demonstration that a 2-fold increase in enzyme activity can reversibly immortalize MEF.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationStimulants of mitosis and activated oncogenes like ras-Val12 generate reactive oxygen species believed to be functionally important in downstream signaling.
“Mitogenic stimulants and activated oncogenes, such as ras-Val12, produce reactive oxygen species that are thought to be functionally important for the downstream signaling mechanisms (46,47).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [46]
Not checked in the free run.
- cites [47] source
Not checked in the free run.
May combine two claims.
PremisecitationWhen cultured at 20% O2, MEFs suffer oxygen poisoning, and growing most MEF strains at 3% O2 prevents senescence.
“Similarly, it has been shown that MEFs in culture at 20% O 2 are subject to oxygen poisoning and senescence can be avoided by growing most MEF strains in 3% O 2 (13).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] source
Not checked in the free run.
May combine two claims.
InterpretationreasoningMEF immortalization occurs after glycolytic activation, which may be achieved directly by PGM or GPI, indirectly by p53DN, or through spontaneous loss of the p53 pathway.
“Immortalization of MEFs thus follows glycolytic activation, which can be mediated directly with PGM or GPI, indirectly with p53DN, or as a consequence of spontaneous abrogation of the p53 pathway.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningEnhanced glycolysis, rather than an unrecognized property of PGM, is the most tenable explanation for immortalization, because catalytically inactive PGM-M mutants had no effect on life span and GPI can also immortalize MEFs.
“The most tenable explanation is enhanced glycolysis, rather than some previously unrecognized property of PGM, because catalytically inactive mutants of PGM-M had no effect on life span, whereas GPI, which lies six catalytic steps upstream in the glycolytic pathway (Fig. 2A) can also immortalize MEFs.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningEarly-passage MEFs' high glycolytic rate offers partial protection from oxidative damage, but oxidative stress ultimately suppresses glycolysis.
“We propose that the high glycolytic rate of early-passage MEFs partially protects against oxidative damage, but that oxidative stress eventually inhibits glycolysis.”
Quote in the paperSubstantial claim- Rests on an assumption: In standard 20% oxygen tissue culture, oxidative stress strongly affects cellular life span.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMost glycolytic enzymes are transcriptionally regulated by HIF-1a.
“Most glycolytic enzymes are transcriptionally regulated by the hypoxia-inducible transcriptional factor HIF-1a (40).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [40] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPGM activity is markedly elevated in numerous cancers, such as lung, colon, liver, and breast.
“The regulation of PGM is poorly understood, although PGM activity is known to be greatly up-regulated in many cancers, including lung, colon, liver, and breast (38,39).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationMouse embryonic fibroblasts grown in 3% oxygen are reported to be virtually immortal and to have less oxidative DNA damage.
“Growing cells under reduced-oxygen conditions can delay senescence and it has recently been reported that MEFs are essentially immortal and show less oxidative DNA damage if propagated in 3% oxygen (13).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] source
Not checked in the free run.
The paper relies on this without support.
Primary mouse embryo fibroblasts lose proliferative capacity after only 10 to 20 population doublings despite having exceptionally long telomeres.
“For example, primary mouse embryo fibroblasts (MEF) lose proliferative capacity after only 10 to 20 population doublings despite having exceptionally long telomeres.”
The paper relies on this without support.
Mouse cells are particularly sensitive to oxidative stress but also escape from the ensuing growth arrest at a relatively high frequency.
“Mouse cells seem to be particularly sensitive to oxidative stress but also escape from the ensuing growth arrest at a relatively high frequency.”
The paper relies on this without support.
PGM catalyses the transfer of phosphate from 3-phosphoglycerate to 2-phosphoglycerate.
“In glycolysis, PGM catalyses the transfer of phosphate from 3-phosphoglycerate to 2-phosphoglycerate (Fig. 2A).”
The paper relies on this without support.
In standard 20% oxygen tissue culture, oxidative stress strongly affects cellular life span.
“It is now appreciated that under standard conditions of tissue culture (i.e., in 20% oxygen), oxidative stress has a major impact on cellular life span.”
The paper relies on this without support.
Mouse embryonic stem cells do not senesce in vitro.
“Most interestingly, mouse embryonic stem cells, which do not senesce in vitro, display naturally high levels of PGM activity and glycolysis even at ambient 20% O 2 (see below).”
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?
TP53 mutations disinhibit glucose metabolism.
“mutations in TP53 disinhibit glucose metabolism.18,19”
From Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells (2024) · cites this paper as [19]
In “Immortalization Correlates with Effects on Glycolysis” (page not available), mouse embryonic fibroblasts expressing dominant-negative p53 showed increased glucose detritiation and lactate production, while induced wild-type p53 reduced PGM activity. This supports the direction of the claim, but the experiments do not establish that TP53 mutations generally disinhibit glucose metabolism. (LLM, conf=0.83)
Experimental — accuracy not yet measuredPancreatic cancers generate substantial lactic acid fluxes, linked to mutations that promote hyper-proliferation.
“pancreatic cancers generate substantial lactic acid fluxes, linked to mutations that promote hyper-proliferation”
From Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells (2024) · cites this paper as [19]
The Introduction (page unavailable) links enhanced aerobic glycolysis in cancer with expression of oncogenes, and the ‘Immortalization Correlates with Effects on Glycolysis’ section reports increased lactate production relative to glucose consumption in engineered mouse cells. The paper does not establish substantial lactic acid flux specifically in pancreatic cancers or link that flux to mutations promoting hyper-proliferation. (LLM, conf=0.83)
Experimental — accuracy not yet measuredOverexpression of phosphoglyceromutase or glucose phosphate isomerase increases glycolytic flux and resistance to oxidative stress, rendering mouse fibroblasts refractory to Ras-induced senescence.
“Consistently with this idea, it has been reported that the overexpression of phosphoglyceromutase or glucose phosphate isomerase increases the glycolytic flux and the resistance to oxidative stress, rendering mouse fibroblasts refractory to Ras-induced senescence (22).”
From Mitochondrial Dysfunction Contributes to Oncogene-Induced Senescence (2009) · cites this paper as [22]
The glycolysis results report that overexpressing either phosphoglycerate mutase (PGM) or glucosephosphate isomerase (GPI) increased glycolytic flux in mouse embryonic fibroblasts. The oxidative-damage results report reduced damage with either enzyme, but the Results section tests resistance to Ras-induced arrest only in PGM-expressing cells. It does not establish that GPI makes the cells refractory to Ras-induced senescence. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSenescent cells can exhibit hyperactive mitochondrial respiration in some contexts.
“senescent cells can exhibit hyperactive mitochondrial respiration (oxidative phosphorylation ) in some contexts.”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [42]
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- Authors
- Kondoh, H., Lleonart, M. E., Gil, J., Wang, J., Degan, P., Peters, G., Martinez, D., Carnero, A., & Beach, D.
- Affiliations
- Cancer Research UK (GB)
- Universitat Autònoma de Barcelona (ES)
- 1Wolfson Institute for Biomedical Research, University College London and
- University College London (GB)
- 3Mutagenesis Laboratory, National Cancer Research Institute-Genova, Genoa, Italy; and
- Instituto de Salud Carlos III (ES)
- Venue
- Cancer Research
- Published
- 2005-01-01
- Volume
- 65
- Issue
- 1
- Pages
- 177-185
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2122826701
- Semantic Scholar
- 3533acdd3761c694734daf0fd88d67e041d3e400
- Cited by
- 647
- References
- 18
- Citations by year
- 2026: 10 · 2025: 16 · 2024: 18 · 2023: 20 · 2022: 29 · 2021: 34 · 2020: 23 · 2019: 20 · 2018: 31 · 2017: 33 · 2016: 36 · 2015: 33 · 2014: 56 · 2013: 37 · 2012: 47
- FWCI
- 15.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Cancer Research UK
- Medical Research Council
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- 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
- Keywords
- phosphoglycerate mutase, phosphoglucose isomerase, glycolytic flux, cellular senescence, cell immortalization, mouse embryonic fibroblasts, mouse embryonic stem cells, p53, short interfering RNA knockdown
- MeSH terms
- Animals, Cell Division, Cell Survival, Cells, Cultured, Embryo, Mammalian, Fibroblasts, Glycolysis, Mice, Inbred C57BL, Phosphoglycerate Mutase, Genes, ras, Mice
About these checks
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.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
Statistics and arithmetic are recomputed, not judged.
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