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| Citrate is a key metabolite involved in cellular energy metabolism, and its levels are often elevated cancer cells. -Citrate is a key substrate for the citric acid cycle (also known as the Krebs cycle or tricarboxylic acid cycle), which is involved in cellular energy metabolism. -Citrate is also involved in the regulation of glycolysis, which is the primary source of energy for many cancer cells. -Citrate has been shown to promote cancer cell growth and survival by regulating various signaling pathways, including the PI3K/AKT pathway. High citrate levels are often associated with poor prognosis in various cancers, including breast, lung, colorectal, prostate, pancreatic, ovarian, and glioblastoma. – Several studies have reported that in certain aggressive tumors, intracellular citrate levels tend to be lower relative to adjacent normal tissues. This is thought to be due to increased utilization of citrate for anabolic processes (e.g., fatty acid synthesis). It was found that the citrate levels of normal human prostate tissue are uniquely much higher than those in malignant prostate tissue (43.1 versus 19.9 mmol/kg). Furthermore, the drastic decrease of citrate level (up to 40-fold in early and 80-fold in advanced stages) in prostate cancer tissues in comparison to normal prostatic tissues is a key characteristic utilized to distinguish between normal and hyperplastic glands. In addition to prostate cancer, citrate levels are significantly decreased in blood of patients with lung, bladder, pancreas and esophagus cancers compared with healthy persons. As a consequence, normal prostate has high concentrations of citrate whereas prostate cancer has low concentrations of citrate. It was widely believed that cancer cells did not take up citrate from the circulation (blood levels of citrate, ~200 μM) and that they met their increased demands for this metabolite via de no synthesis from glutamine (Metallo et al., 2011). This requires a novel reprogramming of the metabolism involving the reversal of the Krebs cycle in which α-ketoglutarate arising from glutamine gets converted into citrate by a process known as “reductive carboxylation.” Indeed, uptake of glutamine resulting from increased expression of multiple glutamine transporters has been associated with cancer cells. Citrate is not only a metabolic intermediate but also a critical signaling node that affects epigenetic regulation (via acetyl-CoA), lipogenesis, and cellular survival pathways. The expression levels of ACLY, SLC25A1, IDH1/2, FASN, and SREBF1 have emerged as important prognostic biomarkers or therapeutic targets in various cancers. -Lower plasma citrate levels have been observed in some cancer patients, suggesting that the tumor’s high metabolic demand may deplete circulating citrate. While many tumors show reduced tissue citrate due to its rapid utilization in anabolic pathways, circulating citrate levels can also be altered, potentially serving as noninvasive biomarkers. 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. Citrate is a gauge of nutrients available for biosynthesis and ATP production generated via oxidative phosphorylation (OXPHOS). In addition, citrate is a key regulatory molecule, which targets (directly or indirectly) catabolic and anabolic pathways (fatty acid β-oxidation (FAO) and FAS, glycolysis, and gluconeogenesis) in a manner such that when one pathway is activated, the other is inhibited. For example, citrate directly inhibits the main regulators of glycolysis, phosphofructokinase-1 (PFK1) and phosphofructokinase-2 (PFK2) [2,3], while it enhances gluconeogenesis by promoting fructose-1,6-biphosphatase (FBPase). Hypothesis that a low citrate level promotes the Warburg effect. |
| 1576- | Citrate, | Targeting citrate as a novel therapeutic strategy in cancer treatment |
| - | Review, | Var, | NA |
| 3140- | VitC, | Vitamin-C-dependent downregulation of the citrate metabolism pathway potentiates pancreatic ductal adenocarcinoma growth arrest |
| - | in-vitro, | PC, | MIA PaCa-2 | - | in-vitro, | Nor, | HEK293 |
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