Icard Philippe, Poulain Laurent, Lincet Hubert
Université de Caen Basse-Normandie, EA 1772, Unité Biologie et Thérapies Innovantes des Cancers Localement Agressifs, et Centre de Lutte Contre le Cancer François Baclesse, Avenue du général Harris, BP5026, F-14076 Caen Cedex 05, France.
Biochim Biophys Acta. 2012 Jan;1825(1):111-6. doi: 10.1016/j.bbcan.2011.10.007. Epub 2011 Nov 10.
Cancers cells strongly stimulate glycolysis and glutaminolysis for their biosynthesis. Pyruvate derived from glucose is preferentially diverted towards the production of lactic acid (Warburg effect). Citrate censors ATP production and controls strategic enzymes of anabolic and catabolic pathways through feedback reactions. Mitochondrial citrate diffuses in the cytosol to restore oxaloacetate and acetyl-CoA. Whereas acetyl-CoA serves de novo lipid synthesis and histone acetylation, OAA is derived towards lactate production via pyruvate and / or a vicious cycle reforming mitochondrial citrate. This cycle allows cancer cells to burn their host's lipid and protein reserves in order to sustain their own biosynthesis pathways. In vitro, citrate has demonstrated anti-cancer properties when administered in excess, sensitizing cancer cells to chemotherapy. Understanding its central role is of particular relevance for the development of new strategies for counteracting cancer cell proliferation and overcoming chemoresistance.
癌细胞强烈刺激糖酵解和谷氨酰胺分解以进行生物合成。源自葡萄糖的丙酮酸优先转向乳酸的产生（瓦伯格效应）。柠檬酸监测ATP的产生，并通过反馈反应控制合成代谢和分解代谢途径的关键酶。线粒体柠檬酸扩散到细胞质中以恢复草酰乙酸和乙酰辅酶A。乙酰辅酶A用于从头合成脂质和组蛋白乙酰化，而草酰乙酸则通过丙酮酸和/或形成线粒体柠檬酸的恶性循环转向乳酸的产生。这个循环使癌细胞能够消耗宿主的脂质和蛋白质储备，以维持自身的生物合成途径。在体外，过量给予柠檬酸已显示出抗癌特性，使癌细胞对化疗敏感。了解其核心作用对于制定对抗癌细胞增殖和克服化疗耐药性的新策略尤为重要。
