Extracellular Citrate Is a Trojan Horse for Cancer Cells

Abstract

The first intermediate in the mitochondrial tricarboxylic acid (TCA) cycle is citrate, which is essential and acts as a metabolic regulator for glycolysis, TCA cycle, gluconeogenesis, and fatty acid synthesis. Within the cytosol, citrate is cleaved by ATP citrate lyase (ACLY) into oxaloacetate (OAA) and acetyl-CoA; OAA can be used for neoglucogenesis or in the TCA cycle, while acetyl-CoA is the precursor of some biosynthetic processes, including the synthesis of fatty acids. Accumulating evidence suggests that citrate is involved in numerous physiological and pathophysiological processes such as inflammation, insulin secretion, neurological disorders, and cancer. Considering the crucial role of citrate to supply the acetyl-CoA pool for fatty acid synthesis and histone acetylation in tumors, in this study we evaluated the effect of citrate added to the growth medium on lipid deposition and histone H4 acetylation in hepatoma cells (HepG2). At low concentration, citrate increased both histone H4 acetylation and lipid deposition; at high concentration, citrate inhibited both, thus suggesting a crucial role of acetyl-CoA availability, which prompted us to investigate the effect of citrate on ACLY. In HepG2 cells, the expression of ACLY is correlated with histone acetylation, which, in turn, depends on citrate concentration. A decrease in H4 acetylation was also observed when citrate was added at a high concentration to immortalized human hepatic cells, whereas ACLY expression was unaffected, indicating a lack of control by histone acetylation. Considering the strong demand for acetyl-CoA but not for OAA in tumor cells, the exogenous citrate would behave like a trojan horse that carries OAA inside the cells and reduces ACLY expression and cellular metabolism. In addition, this study confirmed the already reported dual role of citrate both as a promoter of cell proliferation (at lower concentrations) and as an anticancer agent (at higher concentrations), providing useful tips on the use of citrate for the treatment of tumors.

Hallmarks of Metabolic Reprogramming and Their Role in Viral Pathogenesis

“…The rewiring of the metabolic pathway within the mitochondria involves many metabolites, such as citrate, which is the first intermediate in the TCA cycle [ 52 ]. In metabolic reprogramming, increased exportation of citrate from the mitochondria to the cytosol occurs ( Figure 3 B).…”

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

“…Experimental studies showed that physiological concentration of citrate (200 µM) can sustain the proliferation of various cancer cells, such as prostate, pancreatic and gastric ones [ 130 , 131 ]. Interestingly, citrate concentrations of up to 5 mM can stimulate lipid synthesis and histone acetylation in HepG2 cells, but higher concentrations (10 mM or more) decreased both acetylation and ACLY expression [ 132 ]. Factors influencing the blood concentration of citrate (which is normally around 100–150 µM [ 133 ]) have not been well characterized up to now.…”

Cancer-associated cells release citrate to support tumour metastatic progression

“…This transporter has been cloned from the citrate releasing prostate secretory epithelial cells ( Mazurek et al, 2010 ) and determined to change citrate transport direction, depending on the cell type in which it is expressed ( Mazurek et al, 2010 ; Mycielska et al, 2018 ). Moreover, extracellular citrate can directly promote cancer proliferation ( Petillo et al, 2020 ) and alter metabolism in vitro ( Mycielska et al, 2018 ). In addition, pmCiC was found to be overexpressed in human cancer cells compared with their benign counterparts in vivo, where it was found to correlate with tumour grade, and was particularly increased at the invasion front and metastatic sites of tumours of different origin ( Mycielska et al, 2018 ).…”