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c-Src Promotes Tumorigenesis and Tumor Progression by Activating PFKFB3.

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.
AuthorsHuanhuan 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
JournalCell reports (Cell Rep) Vol. 30 Issue 12 Pg. 4235-4249.e6 (03 24 2020) ISSN: 2211-1247 [Electronic] United States
PMID32209481 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 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)

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