Protein kinase D2 regulates migration and invasion of U87MG glioblastoma cells in vitro

Article


Bernhart, Eva, Damm, Sabine, Wintersperger, Andrea, DeVaney, Trevor, Zimmer, Andreas, Raynham, T., Ireson, Christopher and Sattler, Wolfgang 2013. Protein kinase D2 regulates migration and invasion of U87MG glioblastoma cells in vitro. Experimental Cell Research. 319 (13), pp. 2037-2048.
AuthorsBernhart, Eva, Damm, Sabine, Wintersperger, Andrea, DeVaney, Trevor, Zimmer, Andreas, Raynham, T., Ireson, Christopher and Sattler, Wolfgang
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-JunS73 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.

KeywordsGlioblastoma; Sphingosine-1-phosphate; PRKD2; MAPK; C-Jun; Invasion
JournalExperimental Cell Research
Journal citation319 (13), pp. 2037-2048
ISSN0014-4827
1090-2422
Year2013
PublisherElsevier for Academic Press
Digital Object Identifier (DOI)doi:10.1016/j.yexcr.2013.03.029
Publication dates
Print03 Apr 2013
Publication process dates
Deposited21 Mar 2017
Accepted27 Mar 2013
FunderAustrian Research Promotion Agency (FFG)
Cyathus Exquirere PharmaforschungsGmbH, Vienna, Austria
Austrian Science Fund (FWF)
Austrian National bank
Austrian Research Promotion Agency
Cyathus Exquirere PharmaforschungsGmbH
Austrian Science Fund
Austrian Science Fund
Austrian National bank
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