Characterization of the metabolic changes underlying growth factor angiogenic activation: identification of new potential therapeutic targets.
Angiogenesis is a fundamental process to normal and abnormal tissue growth and repair, which consists of recruiting endothelial cells toward an angiogenic stimulus. The cells subsequently proliferate and differentiate to form endothelial tubes and capillary-like structures. Little is known about the metabolic adaptation of endothelial cells through such a transformation. We studied the metabolic changes of endothelial cell activation by growth factors using human umbilical vein endothelial cells (HUVECs), [1,2-(13)C(2)]-glucose and mass isotopomer distribution analysis. The metabolism of [1,2-(13)C(2)]-glucose by HUVEC allows us to trace many of the main glucose metabolic pathways, including glycogen synthesis, the pentose cycle and the glycolytic pathways. So we established that these pathways were crucial to endothelial cell proliferation under vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) stimulation. A specific VEGF receptor-2 inhibitor demonstrated the importance of glycogen metabolism and pentose cycle pathway. Furthermore, we showed that glycogen was depleted in a low glucose medium, but conserved under hypoxic conditions. Finally, we demonstrated that direct inhibition of key enzymes to glycogen metabolism and pentose phosphate pathways reduced HUVEC viability and migration. In this regard, inhibitors of these pathways have been shown to be effective antitumoral agents. To sum up, our data suggest that the inhibition of metabolic pathways offers a novel and powerful therapeutic approach, which simultaneously inhibits tumor cell proliferation and tumor-induced angiogenesis.
Vizán
Pedro
P
Department of Biochemistry and Molecular Biology, University of Barcelona, Spain.
Sánchez-Tena
Susana
S
Alcarraz-Vizán
Gema
G
Soler
Marta
M
Messeguer
Ramon
R
Pujol
M Dolors
MD
Lee
Wai-Nang Paul
WN
Cascante
Marta
M
D000577:Amides / Q000494:pharmacology; D002247:Carbon Isotopes; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000494:pharmacology / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D005954:Glucosephosphate Dehydrogenase / Q000037:antagonists & inhibitors / Q000502:physiology; D006003:Glycogen / Q000378:metabolism; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D010427:Pentose Phosphate Pathway / Q000502:physiology; D011714:Pyrans / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000502:physiology
C540769:4H-thiopyran-4-one tetrahydro-3,5-bis-((4-nitrophenyl)methylene)-1,1-dioxide; D000577:Amides; D002247:Carbon Isotopes; D007211:Indoles; D011714:Pyrans; D013438:Sulfhydryl Compounds; D042461:Vascular Endothelial Growth Factor A; D005346:Fibroblast Growth Factors; D006003:Glycogen; D005954:Glucosephosphate Dehydrogenase; D024981:Glycogen Phosphorylase; D040301:Vascular Endothelial Growth Factor Receptor-2; C412544:CP 320626; D005947:Glucose