Mitogen-activated protein kinase, ERK1/2, is essential for the induction of vascular endothelial growth factor by ionizing radiation mediated by activator protein-1 in human glioblastoma cells

Vascular Endothelial Growth Factor (VEGF)/Vascular Permeability Factor play s an important role in angiogenesis and cell proliferation of cancer cells. Glioblastoma cells are most malignant and show resistance to radiation the rapy inducing VEGF to cause angiogenesis and brain edema. In the present st udy the regulatory mechanism of the expression of VEGF by ionizing radiatio n was studied in three human glioblastoma cells. Induction of VEGF mRNA by ionizing radiation was dependent on dose and incubation time. Activator pro tein-1 (AP-1) was activated by 10 Gy of ionizing radiation in 1 h in T98G g lioblastoma cells on an electrophoretic mobility shift assay. We constructe d chimeric genes containing various regions of the VEGF promoter gene and t he coding region for chloramphenicol acetyltransferase (CAT) and transientl y transfected them to T98G cells. CAT assay with the VEGF promoter gene con taining an AP-1 site demonstrated that the promoter activity of the VEGF ge ne was enhanced by ionizing radiation. Immunological analysis of the activi ty of mitogen-activated protein kinase, ERK1/2, showed that this activity i s up-regulated by ionizing radiation. These results suggest that ERK1/2 pathway is involved in the up-regulation of VEGF expression ionizing radiation mediated by AP-1, which may lead to f urther neovascularization and proliferation of glioblastoma cells resistant to radiation therapy.