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Protein Kinase C-–Mediated Regulation of Low-Density Lipoprotein Receptor–Related Protein and Urokinase Increases Astrocytoma Invasion

Departments of ¹ Pathology, ² Neuroscience, ³ Neurological Surgery, ⁴ Molecular Physiology and Biological Physics, University of Virginia Health System, Charlottesville, Virginia and ⁵ Center for Cancer Therapeutics, Ottawa Health Research Institute, Ottawa, Ontario, Canada

Requests for reprints: Samson Amos, Department of Pathology, University of Virginia Health System, Charlottesville, VA 22908. Phone: 434-243-4815; Fax: 434-924-2151; E-mail: sa7h{at}virginia.edu.

Aggressive and infiltrative invasion is one of the hallmarks of glioblastoma. Low-density lipoprotein receptor–related protein (LRP) is expressed by glioblastoma, but the role of this receptor in astrocytic tumor invasion remains poorly understood. We show that activation of protein kinase C- (PKC-) phosphorylated and down-regulated LRP expression. Pretreatment of tumor cells with PKC inhibitors, phosphoinositide 3-kinase (PI3K) inhibitor, PKC- small interfering RNA (siRNA), and short hairpin RNA abrogated phorbol 12-myristate 13-acetate–induced down-regulation of LRP and inhibited astrocytic tumor invasion in vitro. In xenograft glioblastoma mouse model and in vitro transmembrane invasion assay, LRP-deficient cells, which secreted high levels of urokinase-type plasminogen activator (uPA), invaded extensively the surrounding normal brain tissue, whereas the LRP-overexpressing and uPA-deficient cells did not invade into the surrounding normal brain. siRNA, targeted against uPA in LRP-deficient clones, attenuated their invasive potential. Taken together, our results strongly suggest the involvement of PKC-/PI3K signaling pathways in the regulation of LRP-mediated astrocytoma invasion. Thus, a strategy of combining small molecule inhibitors of PKC- and PI3K could provide a new treatment paradigm for glioblastomas. [Cancer Res 2007;67(21):10241–51]

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