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The protein kinase C-η isoform induces proliferation in glioblastoma cell lines through an ERK/Elk-1 pathway

Oncogene volume 26, pages 2885–2893 (2007)Cite this article

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.

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Acknowledgements

We thank Teresa Olsen for excellent editorial assistance. The work was supported by R01 Grants NS35122 and CA90851 (IMH) from the National Institutes of Health.

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  1. Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA, USA

    R M Uht, S Amos, P M Martin, A E Riggan & I M Hussaini

  2. Department of Biochemistry and Molecular Genetics, School of Medicine, University of Virginia, Charlottesville, VA, USA

    R M Uht

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Correspondence to R M Uht.

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Uht, R., Amos, S., Martin, P. et al. The protein kinase C-η isoform induces proliferation in glioblastoma cell lines through an ERK/Elk-1 pathway. Oncogene 26, 2885–2893 (2007). https://doi.org/10.1038/sj.onc.1210090

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