Pharmaceutical Sciences Faculty Publications

Title

The Protein Kinase C-η Isoform Induces Proliferation in Glioblastoma Cell Lines Through an ERK/Elk-1 Pathway

Document Type

Article

Publication Date

5-3-2007

Journal Title

Oncogene

ISSN

0950-9232

Volume

26

Issue

20

First Page

2885

Last Page

2893

DOI

http://dx.doi.org/10.1038/sj.onc.1210090

PubMed ID

17146445

Abstract

Glioblastoma multiforme (GBM) is the highest grade of astrocytoma. GBM pathogenesis has been linked to receptor tyrosine kinases and kinases further down signal-transduction pathways – in particular, members of the protein kinase C (PKC) family. The expression and activity of various PKC isoforms are increased in malignant astrocytomas, but not in non-neoplastic astrocytes. This suggests that PKC activity contributes to tumor progression. The level of PKC-η expressed correlates with the degree of phorbol-12-myristate-13-acetate (PMA)-induced proliferation of two glioblastoma cell lines, U-1242 MG and U-251 MG. Normally, U-1242 cells do not express PKC-η, and PMA inhibits their proliferation. Conversely, PMA increases proliferation of U-1242 cells that are stably transfected with PKC-η (U-1242-PKC-η). PMA treatment also stimulates proliferation of U-251 cells, which express PKC-η. Here, we determined that extracellular signal-regulated kinase (ERK) and Elk-1 are downstream targets of PKC-η. Elk-1-mediated transcriptional activity correlates with the PKC-η-mediated mitogenic response. Pretreatment of U-1242-PKC-η cells with inhibitors of PKC or MAPK/ERK kinase (MEK) (bisindolyl maleimide (BIM) or U0126, respectively) blocked both PMA-induced Elk-1 transcriptional activity and PMA-stimulated proliferation. An overexpressed dominant-negative PKC-η reduced the mitogenic response in U-251 cells, as did reduction of Elk-1 by small interfering RNA. Taken together, these results strongly suggest that PKC-η-mediated glioblastoma proliferation involves MEK/mitogen-activated protein (MAP) kinase phosphorylation, activation of ERK and subsequently of Elk-1. Elk-1 target genes involved in GBM proliferative responses have yet to be identified.

Keywords

Cells, protein kinase, PKC-eta, AP-1, ERK, Elk-1, glioblastoma, proliferation