Downregulation of uPA inhibits migration and PI3k/Akt signaling in glioblastoma cells

Nirmala Chandrasekar, Sanjeeva Mohanam, Meena Gujrati, William C. Olivero, Dzung H. Dinh, Jasti S. Rao

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)392-400
Number of pages9
JournalOncogene
Volume22
Issue number3
DOIs
StatePublished - Jan 23 2003

Keywords

  • Antisense uPA
  • Glioblastoma
  • Invasion
  • Migration

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Chandrasekar, N., Mohanam, S., Gujrati, M., Olivero, W. C., Dinh, D. H., & Rao, J. S. (2003). Downregulation of uPA inhibits migration and PI3k/Akt signaling in glioblastoma cells. Oncogene, 22(3), 392-400. https://doi.org/10.1038/sj.onc.1206164