Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Mrfka, M.
Protein kinase D in astrocytic gliomas - a new approach to control tumor growth
Dr.-Studium der medizin. Wissenschaft; Humanmedizin; [ Dissertation ] Medical University of Graz; 2009. pp.57.
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- Autor*innen der Med Uni Graz:
- Mrfka Manuel
- Betreuer*innen:
- Eder Hans
- Sattler Wolfgang
- Altmetrics:
- Abstract:
- Introduction Overexpressed or hyperactivated protein kinases C (PKCs) are among the most distinguished characteristics of malignant brain tumors. Thus, PKCs represent potent targets to interfere with glioma cell motility, invasion and proliferation and may represent new therapeutic avenues. Recently, a new family of serine/threonine protein kinases has been identified, namely protein kinase D1 (PKD1) (formerly known as PKC), PKD2 and PKD3. PKDs are now classified in a novel subgroup of protein kinases within the calcium/calmodulin-dependent kinases. PKD1 expression is high in brain tissue and PKD1 is important in the regulation of cell proliferation and apoptosis and modification of other kinases and plasma membrane proteins in cancer cells. This findings and the facts that the prognosis of patients with glioblastoma are poor despite novel therapies and nothing is known about PKD1 in brain tumors, arranged us to investigate the function of PKD1 in glioblastoma and astrocytic gliomas. Methods The present study was aimed to investigate expression patterns of PKD1 in human astrocytic glioma biopsy material (WHO grade II IV) and A172 glioblastoma cells, to clarify the impact of PKD1 on cell proliferation and to silence PKD1 expression by RNA interference (RNAi) and analyze the consequences on tumor cell growth. Results We have observed that PKD1 expression levels clearly correlate with tumor grading. Immunoreactive PKD1 levels in glioblastoma multiforme are 3-fold higher then in astrocytoma grade II. Futhermore PKD1 is phoshorylated and active in primary glioblatoma cells and can be activated by phorbol-myristate-acetate (PMA) and PDGF (a potent growth factor) in the A172 glioblastoma cell line. Pharmacological inhibition with the indolocarbazole Gö6976 or silencing PKD1 by RNA-interference significantly reduced proliferation rates of glioblastoma cells in vitro. Conclusion In summary the results of the present study indicate that intervention on PKD1 might be promising, useful and novel approach to interfere with the progression of glioblastoma and astrocytic glioma growth.