© 2002 by Society
© 2002 by the Society forNeuro-Oncology
Phosphatidylinositol 3'-kinase and MAPK/ERK kinase 1/2 differentiallyregulate expression of vascular endothelial growth factor in human malignantastrocytoma cells
The Arthur and Sonia Labatt Brain Tumour ResearchCentre, Hospital for Sick Children, Toronto, Ontario, Canada (S.A.W., C.J.M.,A.G.); and Department of Medical Biophysics (S.A.W.,C.J.M., A.G.) and Division of Neurosurgery (A.G.),University of Toronto, Toronto, Ontario, Canada
2 Address correspondence and reprint requests to Abhijit Guha, 4W-446, WesternHospital, 399 Bathurst St., Toronto, Ontario, Canada, M5T 2S8.
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Abstract |
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Malignant astrocytomas are characterized by extensive vascularizationattributed to increased expression of the angiogenic cytokine vascularendothelial growth factor (VEGF). VEGF is elevated in astrocytomas undernormal oxygen conditions and undergoes induction in hypoxic stress. Priorstudies have shown that both the phosphatidylinositol 3-kinase (PI3-kinase)and MEK1/2 (MAPK/ERK kinase 1/2) pathways promote proliferation of astrocytomacells and growth of astrocytic tumors. Whether these pathways regulate growthby modulating angiogenesis as well as proliferation is not clear. In thisstudy, pharmacologic inhibitors were used to specifically inhibit PI3-kinaseand MEK1/2 activity in human malignant astrocytoma cell lines, and theireffects on VEGF expression were determined. Northern blot analysis of VEGFmessenger RNA (mRNA) from cells treated with inhibitors demonstrated cellline-specific responses. The PI3-kinase pathway regulated both the normoxicexpression and hypoxic induction of VEGF in 2 cell lines, whereas MEK1/2regulated only the normoxic expression in the same 2 lines. The third cellline showed no change in VEGF mRNA with inhibition of either of these 2pathways. This study suggests that modulation of signaling pathways implicatedin proliferation of astrocytoma cell lines may have varying effects in vivodepending on the role these pathways play in regulating tumorangiogenesis.
Received January 10, 2002; Accepted April 26, 2002
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