Vitamin‐C‐dependent downregulation of the citrate metabolism pathway potentiates pancreatic ductal adenocarcinoma growth arrest

Autor: Aiora Cenigaonandia‐Campillo, Ana Garcia‐Bautista, Anxo Rio‐Vilariño, Arancha Cebrian, Laura delPuerto, José Antonio Pellicer, José Antonio Gabaldón, Horacio Pérez‐Sánchez, Miguel Carmena‐Bargueño, Carolina Meroño, Javier Traba, María Jesús Fernandez‐Aceñero, Natalia Baños‐Herraiz, Lorena Mozas‐Vivar, Estrella Núñez‐Delicado, Jesús Garcia‐Foncillas, Óscar Aguilera
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Molecular Oncology, Vol 18, Iss 9, Pp 2212-2233 (2024)
Druh dokumentu: article
ISSN: 1878-0261
1574-7891
DOI: 10.1002/1878-0261.13616
Popis: 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.
Databáze: Directory of Open Access Journals
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