Pharmaceutical Sciences Faculty Publications

Title

Protein Kinase C-α Mediated Downregulation of Low-Density Lipoprotein Receptor-related Protein Expression Increases Urokinase Secretion and Astrocytoma Invasion

Document Type

Abstract

Publication Date

10-2006

Journal Title

Neuro-Oncology

Volume

8

Issue

4

First Page

431

Article Number

IN-01

DOI

http://dx.doi.org/10.1215/15228517-2006-020

PubMed Central® ID

PMC1871956

Abstract

Glioblastoma multiforme (GBM) is the most malignant astrocytoma; is characterized by uncontrolled, aggressive cell proliferation and infiltrative growth within the brain; and is resistant to conventional therapy. The molecular and cellular mechanisms governing astrocytic tumor invasion remains poorly understood. We determined the role of low-density lipoprotein receptor-related protein (LRP) in glioblastoma invasive growth. In this study, we demonstrated that activation of protein kinase C (PKC) in astrocytic cell cultures downregulated the expression of LRP and increased the secretion of urokinase (uPA) into conditioned medium. Pretreatment of cell cultures with PKC inhibitors (BIM, Gö 6976) and PI3-kinase inhibitor (LY 294002) and gene silencing with PKCa siRNA abrogated PMAinduced downregulation of LRP, decreased the level of expression of uPA, and inhibited astrocytic tumor cell invasion. Confocal microscopy studies revealed the co-localization of PKC-a and LRP in glioblastoma cell lines. In a Boyden Chamber invasion assay, LRP-deficient glioblastoma cells were more invasive (40%) than LRP-expressing cells, whereas uPA-deficient GBM cells had decreased invasive capacity. Our data show that LRP expression inversely correlates with uPA secretion and GBM invasion. Taken together, our data strongly suggest the involvement of PKCa/PI3 kinase signaling pathways in the regulation of LRP-mediated astrocytoma invasion.

Keywords

C-alpha, protein kinase, lipoprotein, urokinase, astrocytoma invasion