Warburg-associated acidification represses lactic fermentation independently of lactate, contribution from real-time NMR on cell-free systems.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
18 10 2023
18 10 2023
Historique:
received:
21
07
2023
accepted:
12
10
2023
medline:
23
10
2023
pubmed:
19
10
2023
entrez:
18
10
2023
Statut:
epublish
Résumé
Lactate accumulation and acidification in tumours are a cancer hallmark associated with the Warburg effect. Lactic acidosis correlates with cancer malignancy, and the benefit it offers to tumours has been the subject of numerous hypotheses. Strikingly, lactic acidosis enhances cancer cell survival to environmental glucose depletion by repressing high-rate glycolysis and lactic fermentation, and promoting an oxidative metabolism involving reactivated respiration. We used real-time NMR to evaluate how cytosolic lactate accumulation up to 40 mM and acidification up to pH 6.5 individually impact glucose consumption, lactate production and pyruvate evolution in isolated cytosols. We used a reductive cell-free system (CFS) to specifically study cytosolic metabolism independently of other Warburg-regulatory mechanisms found in the cell. We assessed the impact of lactate and acidification on the Warburg metabolism of cancer cytosols, and whether this effect extended to different cytosolic phenotypes of lactic fermentation and cancer. We observed that moderate acidification, independently of lactate concentration, drastically reduces the glucose consumption rate and halts lactate production in different lactic fermentation phenotypes. In parallel, for Warburg-type CFS lactate supplementation induces pyruvate accumulation at control pH, and can maintain a higher cytosolic pyruvate pool at low pH. Altogether, we demonstrate that intracellular acidification accounts for the direct repression of lactic fermentation by the Warburg-associated lactic acidosis.
Identifiants
pubmed: 37853114
doi: 10.1038/s41598-023-44783-3
pii: 10.1038/s41598-023-44783-3
pmc: PMC10584866
doi:
Substances chimiques
Lactic Acid
33X04XA5AT
Pyruvates
0
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
17733Informations de copyright
© 2023. Springer Nature Limited.
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