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SHR Neuro Krebs Kardio Lipid Stoffw Microb
Bernhart, E; Damm, S; Wintersperger, A; DeVaney, T; Zimmer, A; Raynham, T; Ireson, C; Sattler, W.
Protein kinase D2 regulates migration and invasion of U87MG glioblastoma cells in vitro.
Exp Cell Res. 2013; 319(13):2037-2048
Doi: 10.1016/j.yexcr.2013.03.029
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- Führende Autor*innen der Med Uni Graz
- Bernhart Eva Maria
- Damm Sabine
- Sattler Wolfgang
- Co-Autor*innen der Med Uni Graz
- DeVaney Trevor
- Wintersperger Andrea
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- Abstract:
- Glioblastoma multiforme (GBM) is the most common malignant brain tumor, which, despite combined modality treatment, reoccurs and is invariably fatal for affected patients. Recently, a member of the serine/threonine protein kinase D (PRKD) family, PRKD2, was shown to be a potent mediator of glioblastoma growth. Here we studied the role of PRKD2 in U87MG glioblastoma cell migration and invasion in response to sphingosine-1-phosphate (S1P), an activator of PRKD2 and a GBM mitogen. Time-lapse microscopy demonstrated that random cell migration was significantly diminished in response to PRKD2 silencing. The pharmacological PRKD family inhibitor CRT0066101 decreased chemotactic migration and invasion across uncoated or matrigel-coated Transwell inserts. Silencing of PRKD2 attenuated migration and invasion of U87MG cells even more effectively. In terms of downstream signaling, CRT0066101 prevented PRKD2 autophosphorylation and inhibited p44/42 MAPK and to a smaller extent p54/46 JNK and p38 MAPK activation. PRKD2 silencing impaired activation of p44/42 MAPK and p54/46 JNK, downregulated nuclear c-Jun protein levels and decreased c-Jun(S73) phosphorylation without affecting the NFκB pathway. Finally, qPCR array analyses revealed that silencing of PRKD2 downregulates mRNA levels of integrin alpha-2 and -4 (ITGA2 and -4), plasminogen activator urokinase (PLAU), plasminogen activator urokinase receptor (PLAUR), and matrix metallopeptidase 1 (MMP1). Findings of the present study identify PRKD2 as a potential target to interfere with glioblastoma cell migration and invasion, two major determinants contributing to recurrence of glioblastoma after multimodality treatment. Copyright © 2013 Elsevier Inc. All rights reserved.
- Find related publications in this database (using NLM MeSH Indexing)
- Brain Neoplasms - genetics
- Brain Neoplasms - metabolism
- Brain Neoplasms - pathology
- Cell Line, Tumor -
- Cell Movement - drug effects
- Cell Movement - genetics
- Drug Evaluation, Preclinical -
- Gene Expression Regulation, Enzymologic - drug effects
- Gene Expression Regulation, Neoplastic - drug effects
- Glioblastoma - genetics
- Glioblastoma - metabolism
- Glioblastoma - pathology
- Humans -
- Lysophospholipids - pharmacology
- MAP Kinase Signaling System - drug effects
- MAP Kinase Signaling System - genetics
- Neoplasm Invasiveness -
- Protein Kinase Inhibitors - pharmacology
- Protein Kinases - genetics
- Protein Kinases - metabolism
- Protein Kinases - physiology
- Pyrimidines - pharmacology
- RNA Interference - physiology
- RNA, Small Interfering - pharmacology
- Sphingosine - analogs & derivatives
- Sphingosine - pharmacology
- Find related publications in this database (Keywords)
- Glioblastoma
- Sphingosine-l-phosphate
- PRKD2
- MAPK C-Jun
- Invasion