Abstract
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.
Highlights
We have recently discovered that cancer cells need extracellular citrate to support their metabolism [1]
We have shown that extracellular citrate is needed for the metastatic progression of cancer and that citrate is supplied to cancer cells by cancer-associated stroma cells (CACs; [3])
While the ability to use Warburg effect is mandatory for aggressive types of tumours, features such as increased metastatic potential, therapeutic resistance, disease recurrence, and potentially dormant, or circulating, cancer cells seem to be more associated with OXPHOS
Summary
We have recently discovered that cancer cells need extracellular citrate to support their metabolism [1]. Increase in extracellular citrate uptake translates into a decreased intracellular citrate synthesis and allows for an optimal use of metabolic pathways which gives cancer cells several advantages. We will concentrate on two major questions (1) whether extracellular citrate could play a role in inducing the shift from reductive to oxidative functioning of cancer cells and (2) whether organs rich in citrate could form “perfect niches” for metastasis. In this context, we will discuss the role of citrate synthesising cells such as senescent and cancer-associated cells in cancer progression, and the effect of citrate on the function of tumour microenvironment-associated immune cells
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