title: Downregulation of uPA inhibits migration and PI3k/Akt signaling in glioblastoma cells.
abstract: The ability of glioma cells to migrate great distances from a primary tumor mass is the primary cause of tumor recurrence. The urokinase-type plasminogen activator (uPA) is a serine protease that can initiate proteolytic cascades, which result in remodeling of extracellular matrix and basement membrane, allowing cells to move across and through these barriers. The binding between uPA and its receptor uPAR also mediates several signaling events that seem to contribute to the evolution of a migratory phenotype. In this study, we determined how the downregulation of uPA affects the signaling pathways leading to cell migration. Stably transfecting human glioblastoma cells with antisense uPA decreased the amount of cell-bound uPA and disrupted actin cytoskeleton formation and cell migration. The phosphatidylinositol 3-kinase (PI3k) and Akt signaling pathway has been suggested to mediate migration in various cancer cells. The antisense-uPA clones also had less phosphorylated PI3k and Akt than control cells, a finding associated with decreased cell migration, G2/M-phase arrest, and decreased clonogenic survival. Decreased activation of PI3k and the antiapoptotic factor Akt was not sufficient to induce apoptosis in the antisense-uPA clones, but staurosporine sensitized them to apoptosis to a greater extent than control cells. These results indicate that PI3k/Akt pathway is involved in the signaling cascade required to induce cell migration and that uPA has a direct role in regulating migration.
authors.affiliation: Division of Cancer Biology, Department of Biomedical Science, UIC College of Medicine at Peoria, IL 61656, USA.
authors.forename: Nirmala
authors.initials: N
authors.lastname: Chandrasekar
authors.forename: Sanjeeva
authors.initials: S
authors.lastname: Mohanam
authors.forename: Meena
authors.initials: M
authors.lastname: Gujrati
authors.forename: William C
authors.initials: WC
authors.lastname: Olivero
authors.forename: Dzung H
authors.initials: DH
authors.lastname: Dinh
authors.forename: Jasti S
authors.initials: JS
authors.lastname: Rao
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement; D016543:Central Nervous System Neoplasms / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016195:G2 Phase / Q000502:physiology; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008938:Mitosis / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D019311:Staurosporine; D014568:Urokinase-Type Plasminogen Activator; D051020:bcl-X Protein; D020764:cdc42 GTP-Binding Protein; C494811:BCL2L1 protein, human; C494918:AKT1 protein, human