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Review

Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update

1
Medical School, Université Caen Normandie, CHU de Caen, 14000 Caen, France
2
UNICAEN, INSERM U1086 Interdisciplinary Research Unit for Cancer Prevention and Treatment, Normandie Université, 14000 Caen, France
3
Service de Chirurgie Thoracique, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, APHP, Paris-Descartes University, 75014 Paris, France
4
INSERM U1075, COMETE Mobilités: Attention, Orientation, Chronobiologie, Université Caen, 14000 Caen, France
5
School of Medicine, Shenzhen University, Shenzhen 518000, China
6
Oncology Department, Tenon Hospital, Pierre et Marie Curie University, 75020 Paris, France
7
Service de Chirurgie Digestive et Hépato-Biliaire, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, APHP, Paris-Descartes University, 75014 Paris, France
8
Descartes Faculty of Medicine, University of Paris, Paris Center, 75006 Paris, France
9
INSERM U1052, CNRS UMR5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France
10
ISPB, Faculté de Pharmacie, Université Lyon 1, 69373 Lyon, France
11
Department of Infection, Immunity and Inflammation, Institut Cochin, INSERM U1016, CNRS UMR8104, University of Paris, 75014 Paris, France
*
Author to whom correspondence should be addressed.
Academic Editors: Eric Parkinson, Maria E. Mycielska and Sebastian Haferkamp
Int. J. Mol. Sci. 2021, 22(12), 6587; https://doi.org/10.3390/ijms22126587
Received: 19 May 2021 / Revised: 14 June 2021 / Accepted: 16 June 2021 / Published: 19 June 2021
(This article belongs to the Special Issue Cancer Cell Metabolism)
Citrate plays a central role in cancer cells’ metabolism and regulation. Derived from mitochondrial synthesis and/or carboxylation of α-ketoglutarate, it is cleaved by ATP-citrate lyase into acetyl-CoA and oxaloacetate. The rapid turnover of these molecules in proliferative cancer cells maintains a low-level of citrate, precluding its retro-inhibition on glycolytic enzymes. In cancer cells relying on glycolysis, this regulation helps sustain the Warburg effect. In those relying on an oxidative metabolism, fatty acid β-oxidation sustains a high production of citrate, which is still rapidly converted into acetyl-CoA and oxaloacetate, this latter molecule sustaining nucleotide synthesis and gluconeogenesis. Therefore, citrate levels are rarely high in cancer cells. Resistance of cancer cells to targeted therapies, such as tyrosine kinase inhibitors (TKIs), is frequently sustained by aerobic glycolysis and its key oncogenic drivers, such as Ras and its downstream effectors MAPK/ERK and PI3K/Akt. Remarkably, in preclinical cancer models, the administration of high doses of citrate showed various anti-cancer effects, such as the inhibition of glycolysis, the promotion of cytotoxic drugs sensibility and apoptosis, the neutralization of extracellular acidity, and the inhibition of tumors growth and of key signalling pathways (in particular, the IGF-1R/AKT pathway). Therefore, these preclinical results support the testing of the citrate strategy in clinical trials to counteract key oncogenic drivers sustaining cancer development and resistance to anti-cancer therapies. View Full-Text
Keywords: citrate; cancer cells; Warburg effect; ACLY; resistance to therapies citrate; cancer cells; Warburg effect; ACLY; resistance to therapies
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MDPI and ACS Style

Icard, P.; Coquerel, A.; Wu, Z.; Gligorov, J.; Fuks, D.; Fournel, L.; Lincet, H.; Simula, L. Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update. Int. J. Mol. Sci. 2021, 22, 6587. https://doi.org/10.3390/ijms22126587

AMA Style

Icard P, Coquerel A, Wu Z, Gligorov J, Fuks D, Fournel L, Lincet H, Simula L. Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update. International Journal of Molecular Sciences. 2021; 22(12):6587. https://doi.org/10.3390/ijms22126587

Chicago/Turabian Style

Icard, Philippe, Antoine Coquerel, Zherui Wu, Joseph Gligorov, David Fuks, Ludovic Fournel, Hubert Lincet, and Luca Simula. 2021. "Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update" International Journal of Molecular Sciences 22, no. 12: 6587. https://doi.org/10.3390/ijms22126587

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