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

Oncogene volume 22, pages 392–400 (2003)Cite this article

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.

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Abbreviations

ECM:

extracellular matrix

uPA:

urokinase-type plasminogen activator

uPAR:

urokinase-type plasminogen activator receptor

PI3k:

phosphatidylinositol 3-kinase

DMEM:

Dulbecco's modified Eagle medium

FCS:

fetal calf serum

PBS:

phosphate-buffered saline

SDS–PAGE:

sodium dodecyl sulfate–polyacrylamide gel electrophoresis

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Acknowledgements

This work was supported by NIH Grants: CA 75557 and CA 85216 (JS Rao). We thank Karen Minter for preparing the manuscript.

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Authors and Affiliations

  1. Division of Cancer Biology, Departments of Biomedical and Therapeutic Sciences, UIC College of Medicine at Peoria, Peoria, IL, USA

    Nirmala Chandrasekar, Sanjeeva Mohanam & Jasti S Rao

  2. Department of Neuro-Pathology, UIC College of Medicine at Peoria, Peoria, IL, USA

    Meena Gujrati

  3. Department of Neurosurgery, UIC College of Medicine at Peoria, Peoria, IL, USA

    William C Olivero, Dzung H Dinh & Jasti S Rao

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  1. Nirmala Chandrasekar
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  2. Sanjeeva Mohanam
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  6. Jasti S Rao
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Correspondence to Jasti S Rao.

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Chandrasekar, N., Mohanam, S., Gujrati, M. et al. Downregulation of uPA inhibits migration and PI3k/Akt signaling in glioblastoma cells. Oncogene 22, 392–400 (2003). https://doi.org/10.1038/sj.onc.1206164

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