c-Src Promotes Tumorigenesis and Tumor Progression by Activating PFKFB3
c-Src Promotes Tumorigenesis and Tumor Progression by Activating PFKFB3
复制标题
c-Src 通过激活 PFKFB3 促进肿瘤发生和肿瘤进展
DOI：
10.1016/j.celrep.2020.03.005
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发表时间：
2020-03-24
期刊：
影响因子：
8.8
通讯作者：
Li, Qinxi
中科院分区：
文献类型：
--
作者：
Ma, Huanhuan;Zhang, Jia;Li, Qinxi
糖代谢的重编程是肿瘤发生和发展的关键事件。在这里，我们发现活性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。增加的糖酵解中间体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）细胞和用PFKFB3- y194f重组的对应细胞在增殖、迁移和异种移植物形成方面表现出相对受损的能力。此外，PFKFB3-Y194F敲入小鼠显示糖酵解受损，并且这些小鼠与APC（min/+）小鼠交配可减轻APC（min/+）小鼠的自发性结肠癌形成。综上所述，我们确定了c-Src介导糖代谢以满足癌细胞最大限度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。
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(min/+) mice attenuates spontaneous colon cancer formation in APC(min/+) 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.