Luo S, Li Y, Ma R, Liu J, Xu P, Zhang H, Tang K, Ma J, Liu N, Zhang Y, Sun Y, Ji T, Liang X, Yin X, Liu Y, Tong W, Niu Y, Wang N, Wang X, Huang B
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science andTechnology, Wuhan, China.
State Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Oncogene. 2017 Jun 22;36(25):3609-3617. doi: 10.1038/onc.2016.520. Epub 2017 Feb 6.
For cancer cells to proliferate, a balance must be built between biomass-forming, glucose-metabolized intermediates and ATP production. How intrinsic glucose carbon flow regulates this balance remains unclear. Here we show that mitochondrial phosphoenolpyruvate carboxykinase (PCK2), the hub molecule linking tricarboxylic acid (TCA) cycle, glycolysis and gluconeogenesis by conversion of mitochondrial oxaloacetate (OAA) to phosphoenolpyruvate, regulates glucose carbon flow direction in stem-like cells that repopulate tumors (tumor-repopulating cells (TRCs)). PCK2 downregulation accelerated biosynthesis and transportation of citrate from mitochondria to the cytosol, leading to cytosolic glucose carbon flow via OAA-malate-pyruvate and acetyl-CoA-fatty acid pathways in TRCs. On the other hand, downregulating PCK2 hindered fumarate carbon flows in TCA cycle, leading to attenuated oxidative phosphorylation. In pathological terms, PCK2 overexpression slowed TRC growth in vitro and impeded tumorigenesis in vivo. Overall, our work unveiled unexpected glucose carbon flows of TRCs in melanoma that have implications for targeting metabolic aspects of melanoma.
癌细胞要增殖，就必须在生物量形成、葡萄糖代谢中间体和ATP生成之间建立平衡。内在的葡萄糖碳流如何调节这种平衡仍不清楚。在此我们表明，线粒体磷酸烯醇式丙酮酸羧激酶（PCK2），即通过将线粒体草酰乙酸（OAA）转化为磷酸烯醇式丙酮酸来连接三羧酸（TCA）循环、糖酵解和糖异生的枢纽分子，调节可重新填充肿瘤的干细胞样细胞（肿瘤再增殖细胞（TRCs））中的葡萄糖碳流方向。PCK2的下调加速了柠檬酸从线粒体到胞质溶胶的生物合成和转运，导致TRCs中通过OAA-苹果酸-丙酮酸和乙酰辅酶A-脂肪酸途径的胞质葡萄糖碳流。另一方面，下调PCK2阻碍了TCA循环中的富马酸碳流，导致氧化磷酸化减弱。从病理学角度来看，PCK2的过表达减缓了TRCs在体外的生长，并在体内抑制了肿瘤发生。总体而言，我们的工作揭示了黑色素瘤中TRCs意外的葡萄糖碳流，这对靶向黑色素瘤的代谢方面具有重要意义。
