Pim1 kinase is upregulated in glioblastoma multiforme and mediates tumor cell survival
Susann Herzog1, Matthias Alexander Fink1, Kerstin Weitmann1
1Department of Pharmacology/C_DAT (S.H., M.H., M.A.F., T.H., A.B., H.E.M.z.S., H.K.K., B.R., S.B-M.); Institute of Pathology (S.V.); Institute of Pharmacy (C.A.R.); Institute for Community Medicine (K.W., C.H., W.H.); Clinic of Neurosurgery (C.F., M.F., H.S.); Institute of Radiology and Neuroradiology, Universitätsmedizin Greifswald, Greifswald, Germany (S.H., K.K., S.L.); Department of Biomedicine, University of Bergen, Bergen, Norway (E.E., H.M.); Department of Pathology, Haukeland University Hospital, Bergen, Norway (E.E., H.M.).
Background:
The current therapy for glioblastoma multiforme (GBM), the most aggressive and common primary brain tumor of adults, involves surgery and a combined radiochemotherapy that controls tumor progression only for a limited time window. Therefore, the identification of new molecular targets is highly necessary. Inhibition of kinases has become a standard of clinical oncology, and thus the oncogenic kinase Pim1 might represent a promising target for improvement of GBM therapy.
Methods:
Expression of Pim1 and associated signaling molecules was analyzed in human GBM samples, and the potential role of this kinase in patients' prognosis was evaluated. Furthermore, we analyzed the in vivo role of Pim1 in GBM cell growth in an orthotopic mouse model and examined the consequences of Pim1 inhibition in vitro to clarify underlying pathways.
Results:
In comparison with normal brain, a strong upregulation of Pim1 was demonstrated in human GBM samples. Notably, patients with short overall survival showed a significantly higher Pim1 expression compared with GBM patients who lived longer than the median. In vitro experiments with GBM cells and analysis of patients' GBM samples suggest that Pim1 regulation is dependent on epidermal growth factor receptor. Furthermore, inhibition of Pim1 resulted in reduced cell viability accompanied by decreased cell numbers and increased apoptotic cells, as seen by elevated subG1 cell contents and caspase-3 and -9 activation, as well as modulation of several cell cycle or apoptosis regulatory proteins.
Conclusions:
Altogether, Pim1 could be a novel therapeutic target, which should be further analyzed to improve the outcome of patients with aggressive GBM.
Insights
Pim1 kinase is upregulated in glioblastoma multiforme (GBM) and correlates with poor prognosis. Inhibiting Pim1 reduces GBM cell growth and increases apoptosis, suggesting it as a potential therapeutic target for this aggressive brain cancer.
Area of Science:
- Oncology
- Molecular Biology
- Neuro-oncology
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain tumor with limited treatment options.
- Current therapies (surgery, radiochemotherapy) offer only temporary control.
- Novel molecular targets are crucial for improving GBM treatment outcomes.
Purpose of the Study:
- To investigate the role of Pim1 kinase in GBM.
- To evaluate Pim1 as a potential therapeutic target for GBM.
Main Methods:
- Analyzed Pim1 expression in human GBM samples and correlated it with patient prognosis.
- Utilized an orthotopic mouse model to study Pim1's in vivo role in GBM.
- Performed in vitro experiments to assess the effects of Pim1 inhibition on GBM cells.
Main Results:
- Pim1 expression is significantly upregulated in GBM compared to normal brain tissue.
- Higher Pim1 expression correlates with shorter overall survival in GBM patients.
- Pim1 inhibition reduced GBM cell viability, decreased cell numbers, and increased apoptosis via caspase activation and cell cycle/apoptosis protein modulation.
Conclusions:
- Pim1 is a promising novel therapeutic target for glioblastoma multiforme.
- Further research into Pim1 inhibition could lead to improved GBM treatment strategies.
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