PEPCK Coordinates the Regulation of Central Carbon Metabolism to Promote Cancer Cell Growth.
PEPCK Coordinates the Regulation of Central Carbon Metabolism to Promote Cancer Cell Growth.
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DOI：
10.1016/j.molcel.2015.09.025
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发表时间：
2015-11-19
期刊：
影响因子：
16
通讯作者：
Girnun GD
中科院分区：
文献类型：
--
作者：
Montal ED;Dewi R;Bhalla K;Ou L;Hwang BJ;Ropell AE;Gordon C;Liu WJ;DeBerardinis RJ;Sudderth J;Twaddel W;Boros LG;Shroyer KR;Duraisamy S;Drapkin R;Powers RS;Rohde JM;Boxer MB;Wong KK;Girnun GD
磷酸烯醇式丙酮酸羧激酶（PEPCK）是一种重要的生物活性物质。然而，PEPCK也是TCA循环通量的关键调节剂。TCA循环根据细胞需要整合葡萄糖、氨基酸和脂质代谢。此外，对肿瘤生长至关重要的生物合成途径需要TCA循环来加工葡萄糖和谷氨酰胺衍生的碳。我们在此显示PEPCK通过增加葡萄糖和谷氨酰胺对合成代谢的利用，在体外和体内促进癌细胞增殖中具有意想不到的作用。出乎意料的是，PEPCK还增加了从非碳水化合物来源（如谷氨酰胺）合成核糖，这是以前没有描述过的现象。最后，我们发现PEPCK对葡萄糖代谢和细胞增殖的影响部分是通过激活mTORC1介导的。总之，这些数据证明了PEPCK的作用，它将代谢通量和合成代谢途径与癌细胞增殖联系起来。
Phosphoenolpyruvate carboxykinase (PEPCK) is well known for its role in gluconeogenesis. However, PEPCK is also a key regulator of TCA cycle flux. The TCA cycle integrates glucose, amino acid and lipid metabolism depending on cellular needs. In addition, biosynthetic pathways crucial to tumor growth require the TCA cycle for the processing of glucose and glutamine derived carbons. We show here an unexpected role for PEPCK in promoting cancer cell proliferation in vitro and in vivo by increasing glucose and glutamine utilization toward anabolic metabolism. Unexpectedly, PEPCK also increased the synthesis of ribose from non-carbohydrate sources, such as glutamine, a phenomenon not previously described. Finally, we show that the effects of PEPCK on glucose metabolism and cell proliferation are in part mediated via activation of mTORC1. Taken together, these data demonstrate a role for PEPCK that links metabolic flux and anabolic pathways to cancer cell proliferation.