E3 ubiquitin ligase APC/C-Cdh1 accounts for the Warburg effect by linking glycolysis to cell proliferation

Cell proliferation is known to be accompanied by activation of glycolysis. We have recently discovered that the glycolysis-promoting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, isoform 3 (PFKFB3), is degraded by the E3 ubiquitin ligase APC/C-Cdh1, which also degrades cell-cycle prot...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2010-01, Vol.107 (2), p.738-741
Main Authors: Almeida, Angeles, Bolaños, Juan P, Moncada, Salvador
Format: Article
Language:English
Subjects:
Aerobiosis
Biological Sciences
Cadherins - genetics
Cell cycle
Cell Cycle - drug effects
Cell Cycle Proteins - metabolism
Cell Division - drug effects
Cell growth
Cell Line, Tumor
Cell lines
Enzymes
Gene Expression Regulation
Gene Expression Regulation, Neoplastic
Glycolysis
Glycolysis - drug effects
Glycolysis - genetics
HEK293 cells
Humans
Interphase
Kidney - cytology
Kidney - drug effects
Kidney - embryology
Kidney cells
Kinases
Lymphocytes
Mutation
Neuroblastoma - pathology
Neurons
Phosphofructokinase-1 - genetics
Phosphofructokinase-2 - genetics
Phosphofructokinase-2 - metabolism
Proteins
Tretinoin - pharmacology
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
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Summary:Cell proliferation is known to be accompanied by activation of glycolysis. We have recently discovered that the glycolysis-promoting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, isoform 3 (PFKFB3), is degraded by the E3 ubiquitin ligase APC/C-Cdh1, which also degrades cell-cycle proteins. We now show in two different cell types (neoplastic and nonneoplastic) that both proliferation and aerobic glycolysis are prevented by overexpression of Cdh1 and enhanced by its silencing. Furthermore, we have coexpressed Cdh1 with PFKFB3--either wild-type or a mutant form resistant to ubiquitylation by APC/C-Cdh1--or with the glycolytic enzyme 6-phosphofructo-1-kinase and demonstrated that whereas glycolysis is essential for cell proliferation, its initiation in the presence of active Cdh1 does not result in proliferation. Our experiments indicate that the proliferative response, regardless of whether it occurs in normal or neoplastic cells, is dependent on a decrease in the activity of APC/C-Cdh1, which activates both proliferation and glycolysis. These observations have implications for cell proliferation, neoplastic transformation, and the prevention and treatment of cancer.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0913668107