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

Autor: Cenigaonandia-Campillo A; Translational Oncology Division, Oncohealth Institute, IIS-Fundación Jimenez Diaz-UAM (Madrid), Spain., Garcia-Bautista A; Translational Oncology Division, Oncohealth Institute, IIS-Fundación Jimenez Diaz-UAM (Madrid), Spain., Rio-Vilariño A; Translational Oncology Division, Oncohealth Institute, IIS-Fundación Jimenez Diaz-UAM (Madrid), Spain., Cebrian A; Translational Oncology Division, Oncohealth Institute, IIS-Fundación Jimenez Diaz-UAM (Madrid), Spain., Del Puerto L; Translational Oncology Division, Oncohealth Institute, IIS-Fundación Jimenez Diaz-UAM (Madrid), Spain., Pellicer JA; Molecular Recognition and Encapsulation Research Group (REM), Health Sciences Department, Universidad Católica de Murcia (UCAM), Spain., Gabaldón JA; Molecular Recognition and Encapsulation Research Group (REM), Health Sciences Department, Universidad Católica de Murcia (UCAM), Spain., Pérez-Sánchez H; Bioinformatics and High-Performance Computing Research Group (BIO-HPC), Computer Engineering Department, Universidad Católica de Murcia (UCAM), Spain., Carmena-Bargueño M; Bioinformatics and High-Performance Computing Research Group (BIO-HPC), Computer Engineering Department, Universidad Católica de Murcia (UCAM), Spain., Meroño C; Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid (CSIC-UAM), Spain.; Instituto Universitario de Biología Molecular-UAM (IUBM-UAM), Departamento de Biología Molecular, Universidad Autónoma de Madrid, Spain., Traba J; Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid (CSIC-UAM), Spain.; Instituto Universitario de Biología Molecular-UAM (IUBM-UAM), Departamento de Biología Molecular, Universidad Autónoma de Madrid, Spain., Fernandez-Aceñero MJ; Hospital Clínico San Carlos (HCSC), Madrid, Spain., Baños-Herraiz N; Preclinical programe START Madrid-FJD Hospital fundación Jiménez Díaz, Spain., Mozas-Vivar L; Preclinical programe START Madrid-FJD Hospital fundación Jiménez Díaz, Spain., Núñez-Delicado E; Molecular Recognition and Encapsulation Research Group (REM), Health Sciences Department, Universidad Católica de Murcia (UCAM), Spain., Garcia-Foncillas J; Translational Oncology Division, Oncohealth Institute, IIS-Fundación Jimenez Diaz-UAM (Madrid), Spain., Aguilera Ó; Translational Oncology Division, Oncohealth Institute, IIS-Fundación Jimenez Diaz-UAM (Madrid), Spain.; Universidad Católica de Murcia (UCAM), Spain.
Jazyk: angličtina
Zdroj: Molecular oncology [Mol Oncol] 2024 Sep; Vol. 18 (9), pp. 2212-2233. Date of Electronic Publication: 2024 Feb 29.
DOI: 10.1002/1878-0261.13616
Abstrakt: 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.
(© 2024 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
Databáze: MEDLINE
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