title: The reduced concentration of citrate in cancer cells: An indicator of cancer aggressiveness and a possible therapeutic target.
abstract: Proliferating cells reduce their oxidative metabolism and rely more on glycolysis, even in the presence of O2(Warburg effect). This shift in metabolism reduces citrate biosynthesis and diminishes intracellular acidity, both of which promote glycolysis sustaining tumor growth. Because citrate is the donor of acetyl-CoA, its reduced production favors a deacetylation state of proteins favoring resistance to apoptosis and epigenetic changes, both processes contributing to tumor aggressiveness. Citrate levels could be monitored as an indicator of cancer aggressiveness (as already shown in human prostate cancer) and/or could serve as a biomarker for response to therapy. Strategies aiming to increase cytosolic citrate should be developed and tested in humans, knowing that experimental studies have shown that administration of citrate and/or inhibition of ACLY arrest tumor growth, inhibit the expression of the key anti-apoptotic factor Mcl-1, reverse cell dedifferentiation and increase sensibility to cisplatin.
authors.forename: Philippe
authors.lastname: Icard
authors.forename: Hubert
authors.initials: H
authors.lastname: Lincet
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000105:Acetyl Coenzyme A / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D019343:Citric Acid / Q000378:metabolism* / Q000627:therapeutic use; D002952:Citric Acid Cycle / Q000187:drug effects* / Q000235:genetics; D044127:Epigenesis, Genetic; D006019:Glycolysis / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019343:Citric Acid; D000105:Acetyl Coenzyme A; D001275:ATP Citrate (pro-S)-Lyase
keywords: ATP-citrate lyase; Citrate; Hydroxycitrate; Lipoic acid; Prognosis biomarker; Tumor aggressiveness; Warburg effect