State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
Metabolomics Core Laboratory, Healthy Aging Research Center, Chang Gung University, Taoyuan City 33302, Taiwan.
Cell Rep. 2020 Mar 24;30(12):4235-4249.e6. doi: 10.1016/j.celrep.2020.03.005.
Reprogramming of glucose metabolism is a key event in tumorigenesis and progression. Here, we show that active c-Src stimulates glycolysis by phosphorylating (Tyr194) and activating PFKFB3, a key enzyme that boosts glycolysis by producing fructose-2,6-bisphosphate and activating PFK1. Increased glycolysis intermediates replenish non-oxidative pentose phosphate pathway (PPP) and serine pathway for biosynthesis of cancer cells. PFKFB3 knockout (KO) cells and their counterpart reconstituted with PFKFB3-Y194F show comparably impaired abilities for proliferation, migration, and xenograft formation. Furthermore, PFKFB3-Y194F knockin mice show impaired glycolysis and, mating of these mice with APC mice attenuates spontaneous colon cancer formation in APC mice. In summary, we identify a specific mechanism by which c-Src mediates glucose metabolism to meet cancer cells' requirements for maximal biosynthesis and proliferation. The PFKFB3-Tyr194 phosphorylation level highly correlates with c-Src activity in clinical tumor samples, indicating its potential as an evaluation for tumor prognosis.
葡萄糖代谢的重编程是肿瘤发生和进展的关键事件。在这里，我们表明，活性 c-Src 通过磷酸化（Tyr194）和激活 PFKFB3 来刺激糖酵解，PFKFB3 是一种通过产生果糖-2,6-二磷酸和激活 PFK1 来促进糖酵解的关键酶。增加的糖酵解中间产物补充非氧化戊糖磷酸途径（PPP）和丝氨酸途径，用于癌细胞的生物合成。PFKFB3 敲除（KO）细胞及其用 PFKFB3-Y194F 重建的对应物显示出增殖、迁移和异种移植物形成能力相当受损。此外，PFKFB3-Y194F 敲入小鼠显示出受损的糖酵解，并且这些小鼠与 APC 小鼠交配会减弱 APC 小鼠中自发性结肠癌的形成。总之，我们确定了 c-Src 介导葡萄糖代谢以满足癌细胞最大生物合成和增殖需求的特定机制。在临床肿瘤样本中，PFKFB3-Tyr194 磷酸化水平与 c-Src 活性高度相关，表明其作为肿瘤预后评估的潜力。
