c-Src Promotes Tumorigenesis and Tumor Progression by Activating PFKFB3.
Ma Huanhuan,Zhang Jia,Zhou Lin,Wen Shixiong,Tang Hsiang-Yu,Jiang Bin,Zhang Fengqiong,Suleman Muhammad,Sun Dachao,Chen Ai,Zhao Wentao,Lin Furong,Tsau Ming-Tong,Shih Lu-Min,Xie Changchuan,Li Xiaotong,Lin Donghai,Hung Li-Man,Cheng Mei-Ling,Li Qinxi
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.