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

Abstract

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.

Simulated Galactic Cosmic Rays Modify Mitochondrial Metabolism in Osteoclasts, Increase Osteoclastogenesis and Cause Trabecular Bone Loss in Mice

“…This intermediate regulates the ATP supply through acetyl CoA’s entry to the TCA cycle [ 71 ]. Thus, such decreases in the utilization of these substrates could indicate a probable allosteric downregulation of TCA cycle enzymes due to high levels of ATP production following GCR exposure in the preOCs [ 72 ]. Succinic acid not only provides FADH2 for ATP production via oxidative phosphorylation but also directly links the TCA cycle to mitochondrial ETC through succinate dehydrogenase complex (Complex II) [ 73 , 74 ].…”

A “Weird” Mitochondrial Fatty Acid Oxidation as a Metabolic “Secret” of Cancer

“…Upregulation of ACLY could be one of the key events in malignant cell transformation. Icard et al hypothesized that upregulation of ACLY is responsible for maintaining low cytosolic citrate levels in cancer cells, favoring enhancement of glycolysis (which would be inhibited by high citrate) and activation of oncogenic drivers, such as the PI3K/Akt and WNT/ β -catenin pathway [ 202 ]. Indeed, citrate production may not be a key characteristic of cancer cells, but increased citrate utilization may be one of the key events in the transformation of cancer cells.…”

Metabolic Swifts Govern Normal and Malignant B Cell Lymphopoiesis

“…Aerobic glycolysis, or the Warburg effect, summarizes the extramitochondrial utilization of glucose for inefficient energy production in the form of ATP, though with the major benefit of redox state improvement, NADPH production and active anabolism (nucleotides through the pentose phosphate pathway (PPP), phospholipids, etc.). Mitochondrial OxPhos on the other hand involves the sequential oxidation of carbonic molecules, glucose in the form of pyruvate, fatty acids, amino acids, etc., through the mitochondrial tricarboxylic acid cycle (TCA) [ 12 ]. Electrons that are released inside TCA are carried by coenzyme molecules, namely FADH2 and NADH, towards a mitochondrial membrane-bound four-proteinic complex sequence, the electron transport chain (ETC) [ 13 ].…”

“…pathway (PPP), phospholipids, etc.). Mitochondrial OxPhos on the other hand involves the sequential oxidation of carbonic molecules, glucose in the form of pyruvate, fatty acids, amino acids, etc., through the mitochondrial tricarboxylic acid cycle (TCA) [12]. Electrons that are released inside TCA are carried by coenzyme molecules, namely FADH2 and NADH, towards a mitochondrial membrane-bound four-proteinic complex sequence, the electron transport chain (ETC) [13].…”