c-Src Promotes Tumorigenesis and Tumor Progression by Activating PFKFB3
- Cell Rep. 2020 Mar 24;30(12):4235-4249.e6. doi: 10.1016/j.celrep.2020.03.005.
- 1. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
- 2. Metabolomics Core Laboratory, Healthy Aging Research Center, Chang Gung University, Taoyuan City 33302, Taiwan.
- 3. Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, China.
- 4. Department and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan 33302, Taiwan; Center for Healthy and Aging Research, Chang Gung University, Taoyuan City 33302, Taiwan; Kidney Research Center, Chang Gung Memorial Hospital, Taoyuan City 33302, Taiwan. Electronic address: [email protected].
- 5. Metabolomics Core Laboratory, Healthy Aging Research Center, Chang Gung University, Taoyuan City 33302, Taiwan; Department and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan 33302, Taiwan; Clinical Metabolomics Core Laboratory, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan. Electronic address: [email protected].
- 6. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; Cancer Research Center of Xiamen University, Xiamen, Fujian 361102, China. Electronic address: [email protected].
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 APCmin/+ mice attenuates spontaneous colon Cancer formation in APCmin/+ 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.