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Glioma Cells Deficient in Urokinase Plaminogen Activator Receptor Expression Are Susceptible to Tumor Necrosis Factor--related Apoptosis-inducing Ligand-induced Apoptosis¹

Division of Cancer Biology, Departments of Biomedical and Therapeutic Sciences [B. K., J. S. R.], Neurosurgery [D. H. D., W. C. O., J. S. R.], and Neuropathology [M. G.], University of Illinois College of Medicine at Peoria, Illinois 61656; Cytokine Research Laboratory, Department of Bioimmunotherapy, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [B. D., B. A.]; and Department of Propedeutic Surgery, Athens University School of Medicine, Athens 11526, Greece [G. K.]

Purpose: The urokinase plasminogen activation system comprises the ligand urokinase plasminogen activator and the receptor urokinase plasminogen activator receptor (uPAR), which play an important role in the activation of matrix-degrading enzymes that enhance the invasion of cancer cells. Earlier studies have indicated that SNB19 glioblastoma cells expressing antisense uPAR constructs lose their invasive properties when injected in vivo. Additional observations indicated that injected antisense uPAR:SNB19 cells were being lost through apoptotic elimination.

Experimental Design: SNB19, Vector, and SNB19:asuPAR were analyzed to determine cytotoxicity of tumor necrosis factor--related apoptosis-inducing ligand (TRAIL), receptor expression, and underlying signaling pathways using flow cytometry, immunohistochemistry, RNase protection assay, and c-Jun-NH₂-terminal kinase activity.

Results: This study elucidated the susceptibility of antisense uPAR:SNB19 cells to TRAIL under certain experimental conditions in vitro. These uPAR-deficient transfected cells had higher levels of the TRAIL receptors DR4 and DR5 than did the control and vector population as detected by flow cytometry. An RNase protection assay confirmed the elevation of DR4 and DR5 mRNA in the antisense uPAR cells.

Conclusions: These findings provide preliminary evidence of a link between TRAIL-induced apoptosis and cell cycle progression in antisense uPAR:SNB 19 cells.

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