| Source: |
| Type: |
| 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. |
| Cyclooxygenase (COX)-2 overexpression has been noted in various cancers.
PI3Ks/AKT pathways are over-activated in several types of cancers. EGFR altered activity has been noted in various pathological conditions. However, its regulation is an important step in the inhibition of cancer. In this regard, EGCG shows a pivotal role in the inhibition of EGFR activity. Activating protein-1 transcription factor has been associated with pathogenesis including cancer. Activation of the sonic hedgehog (Shh) pathway is required for the growth of numerous tissues and organs and recent evidence indicates that this pathway is often recruited to stimulate growth of cancer stem cells (CSCs) and to orchestrate the reprogramming of cancer cells via epithelial mesenchymal transition (EMT). Increased expression of Nanog has been associated with the aggressive nature of certain cancers, highlighting its role in promoting cancer stem cell characteristics. The aberrant hedgehog (Hh)/GLI signaling pathway causes the formation and progression of a variety of tumors. The process of cell apoptosis is often accompanied by the destruction of mitochondrial transmembrane potential, which is widely regarded as one of the earliest events in the process of cell apoptosis. Human malignancies frequently exhibit mutations in the TGF-β pathway, and overactivation of this system is linked to tumor growth by promoting angiogenesis and inhibiting the innate and adaptive antitumor immune responses50. Several studies have demonstrated that high cyclin D1 expression was observed in cancers including breast, lung, prostate, lymph node and colorectal cancers [23–25]. The oncogene c-myc, which is frequently over-expressed in cancer cells, is involved in the transactivation of most of the glycolytic enzymes including lactate dehydrogenase A (LDHA) and the glucose transporter GLUT1 [51,52]. Thus, c-myc activation is a likely candidate to promote the enhanced glucose uptake and lactate release in the proliferating cancer cell. Vimentin is overexpressed in various epithelial cancers, including prostate cancer, gastrointestinal tumors, tumors of the central nervous system, breast cancer, malignant melanoma, and lung cancer. Vimentin’s overexpression in cancer correlates well with accelerated tumor growth, invasion, and poor prognosis; however, the role of vimentin in cancer progression remains obscure. Heat shock proteins (HSPs) are normally induced under environmental stress to serve as chaperones for maintenance of correct protein folding but they are often overexpressed in many cancers, including breast cancer. Since NQO1 is highly expressed in many solid tumors, including via upregulation of Nrf2, the design of compounds activated by NQO1 and NQO1-targeted drug delivery have been active areas of research. Since increased Nrf2 gene expression is one of the main mechanisms of cancer cells in resisting chemotherapeutic drugs and survival in oxidative conditions; finding compounds with the ability to suppress Nrf2 gene expression with minimum side effects can be considered an important strategy for increasing the sensitivity of cancer cells to chemotherapy. Overexpression of c-met stimulates proliferation, migration and invasion in various types of cancer including prostate cancer. Overexpression of TGFα and EGFR by many carcinomas correlates with the development of cancer metastasis, resistance to chemotherapy and poor prognosis. More than 50% of human cancers have a mutated nonfunctional p53. |
| 1576- | Citrate, | Targeting citrate as a novel therapeutic strategy in cancer treatment |
| - | Review, | Var, | NA |
Query results interpretion may depend on "conditions" listed in the research papers. Such Conditions may include : -low or high Dose -format for product, such as nano of lipid formations -different cell line effects -synergies with other products -if effect was for normal or cancerous cells
Filter Conditions: Pro/AntiFlg:% IllCat:% CanType:26 Cells:% prod#:% Target#:951 State#:% Dir#:1
wNotes=0 sortOrder:rid,rpid