Department of Surgery, University Hospital Regensburg, Regensburg, Germany.
Institute of Functional Genomics, University of Regensburg, Regensburg, Germany.
Cancer Res. 2018 May 15;78(10):2513-2523. doi: 10.1158/0008-5472.CAN-17-2959. Epub 2018 Mar 6.
Glycolysis and fatty acid synthesis are highly active in cancer cells through cytosolic citrate metabolism, with intracellular citrate primarily derived from either glucose or glutamine via the tricarboxylic acid cycle. We show here that extracellular citrate is supplied to cancer cells through a plasma membrane-specific variant of the mitochondrial citrate transporter (pmCiC). Metabolomic analysis revealed that citrate uptake broadly affected cancer cell metabolism through citrate-dependent metabolic pathways. Treatment with gluconate specifically blocked pmCiC and decreased tumor growth in murine xenografts of human pancreatic cancer. This treatment altered metabolism within tumors, including fatty acid metabolism. High expression of pmCiC was associated with invasion and advanced tumor stage across many human cancers. These findings support the exploration of extracellular citrate transport as a novel potential target for cancer therapy. Uptake of extracellular citrate through pmCiC can be blocked with gluconate to reduce tumor growth and to alter metabolic characteristics of tumor tissue. .
癌细胞中的糖酵解和脂肪酸合成通过细胞质柠檬酸代谢高度活跃，细胞内柠檬酸主要来自葡萄糖或谷氨酰胺通过三羧酸循环。我们在这里表明，细胞外柠檬酸通过线粒体柠檬酸转运蛋白 (pmCiC) 的质膜特异性变体供应给癌细胞。代谢组学分析表明，柠檬酸摄取通过柠檬酸依赖的代谢途径广泛影响癌细胞代谢。用葡萄糖酸处理特异性阻断 pmCiC 并减少人胰腺癌细胞的小鼠异种移植物中的肿瘤生长。这种治疗改变了肿瘤内的代谢，包括脂肪酸代谢。pmCiC 的高表达与许多人类癌症的侵袭和晚期肿瘤阶段有关。这些发现支持将细胞外柠檬酸转运作为癌症治疗的新潜在靶点进行探索。通过 pmCiC 摄取细胞外柠檬酸可以用葡萄糖酸阻断，以减少肿瘤生长并改变肿瘤组织的代谢特征。
