Abstract
Increased need for glycolysis and glucose uptake for ATP production is observed in tumor cells, particularly in cells lacking of oxygen supply. Because glucose is transported from blood to tumor, glucose molecules must be delivered across glucose transporters of the vascular endothelium and tumor cells. Here we found that glioma suffered from hypoxic insults can secrete factor(s) to regulate glucose transporter expression in brain endothelium. It was found that conditioned medium from rat C6 glioma cells under hypoxia up-regulated glucose transporter type 1 (GLUT1) expression in rat brain endothelial cells, whereas conditioned medium from C6 cells under normoxia caused no significant effect. We further investigated whether the observed potentiating effect was caused by vascular endothelial growth factor (VEGF) production from C6 cells, because secreted VEGF was markedly increased under hypoxic condition. By transfection of C6 cells with VEGF small interfering RNA, it was found that conditioned medium from transfected cells under hypoxia no longer up-regulated GLUT1 expression of endothelial cells. Moreover, the addition of VEGF-neutralizing antibody to the hypoxic conditioned medium could also exert similar inhibitory effects. Furthermore, it was found that the VEGF-induced increase of GLUT1 expression in endothelial cells was mediated by the phosphoinositide-3 kinase/Akt pathway. Our results indicate that hypoxic brain glioma may secrete VEGF to increase glucose transport across blood-brain barrier.
Footnotes
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The work was supported by research grants from the National Science Council of Taiwan.
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ABBREVIATIONS: GLUT, glucose transporter; BBB, blood-brain barrier; CRE, cAMP-responsive element; CB, cytochalasin B; CM, conditioned medium; Hx, hypoxia; IGF, insulin-like growth factor; Nx, normoxia; PI3K, phosphoinositide-3 kinase; RBEC, rat brain endothelial cell; VEGF, vascular endothelial growth factor; ELISA, enzyme-linked immunosorbent assay; PBS, phosphate-buffered saline; siRNA, small interfering RNA; PCR, polymerase chain reaction; rh, recombinant human; LY294002, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one.
- Received June 7, 2007.
- Accepted October 17, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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