Extracellular citrate and metabolic adaptations of cancer cells

It is well established that cancer cells acquire energy via the Warburg effect and oxidative phosphorylation. Citrate is considered to play a crucial role in cancer metabolism by virtue of its production in the reverse Krebs cycle from glutamine. Here, we review the evidence that extracellular citra...

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Bibliographic Details
Published in:Cancer and metastasis reviews 2021-12, Vol.40 (4), p.1073-1091
Main Authors: Parkinson, E. Kenneth, Adamski, Jerzy, Zahn, Grit, Gaumann, Andreas, Flores-Borja, Fabian, Ziegler, Christine, Mycielska, Maria E.
Format: Article
Language:English
Subjects:
Adaptation
Biomedical and Life Sciences
Biomedicine
Cancer
Cancer cells
Cancer Research
Citrates
Citric acid
Citric Acid - metabolism
Citric Acid Cycle
Glutamine
Humans
Liver cancer
Metabolic pathways
Metabolism
Metabolites
Metastases
Metastasis
Microenvironments
Neoplasms - metabolism
Oncology
Oxidative Phosphorylation
Phosphorylation
Physiological aspects
Reviews
Tricarboxylic acid cycle
Tumor microenvironment
Tumor Microenvironment - physiology
Tumors
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Summary:It is well established that cancer cells acquire energy via the Warburg effect and oxidative phosphorylation. Citrate is considered to play a crucial role in cancer metabolism by virtue of its production in the reverse Krebs cycle from glutamine. Here, we review the evidence that extracellular citrate is one of the key metabolites of the metabolic pathways present in cancer cells. We review the different mechanisms by which pathways involved in keeping redox balance respond to the need of intracellular citrate synthesis under different extracellular metabolic conditions. In this context, we further discuss the hypothesis that extracellular citrate plays a role in switching between oxidative phosphorylation and the Warburg effect while citrate uptake enhances metastatic activities and therapy resistance. We also present the possibility that organs rich in citrate such as the liver, brain and bones might form a perfect niche for the secondary tumour growth and improve survival of colonising cancer cells. Consistently, metabolic support provided by cancer-associated and senescent cells is also discussed. Finally, we highlight evidence on the role of citrate on immune cells and its potential to modulate the biological functions of pro- and anti-tumour immune cells in the tumour microenvironment. Collectively, we review intriguing evidence supporting the potential role of extracellular citrate in the regulation of the overall cancer metabolism and metastatic activity.
ISSN:0167-7659
1573-7233
DOI:10.1007/s10555-021-10007-1