Vitamin-C-dependent downregulation of the citrate metabolism pathway potentiates pancreatic ductal adenocarcinoma growth arrest.
PDAC
citrate synthase
gemcitabine
metabolism
vitamin C
Journal
Molecular oncology
ISSN: 1878-0261
Titre abrégé: Mol Oncol
Pays: United States
ID NLM: 101308230
Informations de publication
Date de publication:
29 Feb 2024
29 Feb 2024
Historique:
revised:
17
01
2024
received:
31
07
2023
accepted:
15
02
2024
medline:
1
3
2024
pubmed:
1
3
2024
entrez:
1
3
2024
Statut:
aheadofprint
Résumé
In pancreatic ductal adenocarcinoma (PDAC), metabolic rewiring and resistance to standard therapy are closely associated. PDAC cells show enormous requirements for glucose-derived citrate, the first rate-limiting metabolite in the synthesis of new lipids. Both the expression and activity of citrate synthase (CS) are extraordinarily upregulated in PDAC. However, no previous relationship between gemcitabine response and citrate metabolism has been documented in pancreatic cancer. Here, we report for the first time that pharmacological doses of vitamin C are capable of exerting an inhibitory action on the activity of CS, reducing glucose-derived citrate levels. Moreover, ascorbate targets citrate metabolism towards the de novo lipogenesis pathway, impairing fatty acid synthase (FASN) and ATP citrate lyase (ACLY) expression. Lowered citrate availability was found to be directly associated with diminished proliferation and, remarkably, enhanced gemcitabine response. Moreover, the deregulated citrate-derived lipogenic pathway correlated with a remarkable decrease in extracellular pH through inhibition of lactate dehydrogenase (LDH) and overall reduced glycolytic metabolism. Modulation of citric acid metabolism in highly chemoresistant pancreatic adenocarcinoma, through molecules such as vitamin C, could be considered as a future clinical option to improve patient response to standard chemotherapy regimens.
Identifiants
pubmed: 38425123
doi: 10.1002/1878-0261.13616
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Universidad Católica San Antonio de Murcia
Organisme : O.N.G Otro Mundo Es Posible
Organisme : Ministerio de Ciencia y Tecnología
Organisme : Centro para el Desarrollo Tecnológico Industrial
Informations de copyright
© 2024 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
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