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c-Src Promotes Tumorigenesis and Tumor Progression by Activating PFKFB3
Huanhuan Ma1, Jia Zhang1, Lin Zhou1
1State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
Cell Reports
|March 27, 2020
Summary
Active c-Src stimulates cancer cell glycolysis by phosphorylating and activating PFKFB3. This reprogramming of glucose metabolism fuels cancer cell biosynthesis and proliferation, highlighting PFKFB3-Tyr194 as a potential prognostic marker.
Area of Science:
- Oncology
- Cancer Metabolism
- Molecular Biology
Background:
- Tumorigenesis involves significant reprogramming of glucose metabolism.
- The enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) plays a critical role in regulating glycolysis.
Purpose of the Study:
- To elucidate the mechanism by which c-Src influences glucose metabolism in cancer cells.
- To investigate the role of PFKFB3 phosphorylation at Tyr194 in cancer progression.
Main Methods:
- Utilized PFKFB3 knockout (KO) and knockin cell/mouse models (PFKFB3-Y194F).
- Assessed cellular proliferation, migration, and xenograft formation.
- Examined glycolysis flux and cancer formation in genetically engineered mouse models.
Main Results:
- Active c-Src phosphorylates and activates PFKFB3 at Tyr194, enhancing glycolysis.
- PFKFB3 activation boosts glycolysis intermediates for biosynthesis pathways (pentose phosphate and serine pathways).
- PFKFB3-Y194F mutation or KO impairs cancer cell proliferation, migration, and xenograft formation; PFKFB3-Tyr194 phosphorylation correlates with c-Src activity in clinical samples.
Conclusions:
- c-Src-mediated PFKFB3 phosphorylation at Tyr194 is a key mechanism driving cancer cell glycolysis, biosynthesis, and proliferation.
- PFKFB3-Tyr194 phosphorylation serves as a potential prognostic biomarker for cancer.
- Targeting this pathway could offer therapeutic strategies for cancer treatment.
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