Montal Emily D, Dewi Ruby, Bhalla Kavita, Ou Lihui, Hwang Bor Jang, Ropell Ashley E, Gordon Chris, Liu Wan-Ju, DeBerardinis Ralph J, Sudderth Jessica, Twaddel William, Boros Laszlo G, Shroyer Kenneth R, Duraisamy Sekhar, Drapkin Ronny, Powers R Scott, Rohde Jason M, Boxer Matthew B, Wong Kwok-Kin, Girnun Geoffrey D
Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA.
Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Mol Cell. 2015 Nov 19;60(4):571-83. doi: 10.1016/j.molcel.2015.09.025. Epub 2015 Oct 17.
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.
磷酸烯醇式丙酮酸羧激酶（PEPCK）因其在糖异生中的作用而广为人知。然而，PEPCK也是三羧酸循环通量的关键调节因子。三羧酸循环根据细胞需求整合葡萄糖、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三羧酸循环来处理葡萄糖和谷氨酰胺衍生的碳源。我们在此展示了PEPCK在体外和体内通过增加葡萄糖和谷氨酰胺向合成代谢的利用来促进癌细胞增殖的意外作用。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）合成核糖的过程，这是此前未描述过的现象。最后，我们表明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。综上所述，这些数据证明了PEPCK在将代谢通量和合成代谢途径与癌细胞增殖联系起来方面的作用。
