Abstract |
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.
|
Authors | Huanhuan Ma, Jia Zhang, Lin Zhou, Shixiong Wen, Hsiang-Yu Tang, Bin Jiang, Fengqiong Zhang, Muhammad Suleman, Dachao Sun, Ai Chen, Wentao Zhao, Furong Lin, Ming-Tong Tsau, Lu-Min Shih, Changchuan Xie, Xiaotong Li, Donghai Lin, Li-Man Hung, Mei-Ling Cheng, Qinxi Li |
Journal | Cell reports
(Cell Rep)
Vol. 30
Issue 12
Pg. 4235-4249.e6
(03 24 2020)
ISSN: 2211-1247 [Electronic] United States |
PMID | 32209481
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Copyright | Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved. |
Chemical References |
- Reactive Oxygen Species
- Phosphotyrosine
- PFKFB3 protein, human
- Phosphofructokinase-2
- Proto-Oncogene Proteins pp60(c-src)
|
Topics |
- Animals
- Carcinogenesis
(metabolism, pathology)
- Colonic Neoplasms
(genetics)
- Disease Progression
- Enzyme Activation
- Glycolysis
- HCT116 Cells
- HEK293 Cells
- Humans
- Mice, Inbred C57BL
- Mutation
(genetics)
- Neoplasms
(metabolism, pathology)
- Phosphofructokinase-2
(metabolism)
- Phosphorylation
- Phosphotyrosine
(metabolism)
- Protein Binding
- Proto-Oncogene Proteins pp60(c-src)
(metabolism)
- Reactive Oxygen Species
(metabolism)
|