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 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.
Almeida
Angeles
A
Hospital Universitario de Salamanca, Instituto de Estudios de Ciencias de la Salud de Castilla y Leon, 37007 Salamanca, Spain.
Bolaños
Juan P
JP
Moncada
Salvador
S
D000332:Aerobiosis; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000196:embryology; D009447:Neuroblastoma / Q000473:pathology; D010732:Phosphofructokinase-1 / Q000235:genetics; D025481:Phosphofructokinase-2 / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D018797:Cell Cycle Proteins; D014212:Tretinoin; D044767:Ubiquitin-Protein Ligases; C107345:PFKFB3 protein, human; D025481:Phosphofructokinase-2; D010732:Phosphofructokinase-1