Abstract
Despite comprehensive therapy and extensive research, glioblastoma (GBM) still represents the most aggressive brain tumor in adults. Glioma stem cells (GSCs) are thought to play a major role in tumor progression and resistance of GBM cells to radiochemotherapy. The PIM1 kinase has become a focus in cancer research. We have previously demonstrated that PIM1 is involved in survival of GBM cells and in GBM growth in a mouse model. However, little is known about the importance of PIM1 in cancer stem cells. Here, we report on the role of PIM1 in GBM stem cell behavior and killing. PIM1 inhibition negatively regulates the protein expression of the stem cell markers CD133 and Nestin in GBM cells (LN-18, U-87 MG). In contrast, CD44 and the astrocytic differentiation marker GFAP were up-regulated. Furthermore, PIM1 expression was increased in neurospheres as a model of GBM stem-like cells. Treatment of neurospheres with PIM1 inhibitors (TCS PIM1-1, Quercetagetin, and LY294002) diminished the cell viability associated with reduced DNA synthesis rate, increased caspase 3 activity, decreased PCNA protein expression, and reduced neurosphere formation. Our results indicate that PIM1 affects the glioblastoma stem cell behavior, and its inhibition kills glioblastoma stem-like cells, pointing to PIM1 targeting as a potential anti-glioblastoma therapy.
Highlights
Glioblastoma (GBM) represents the most common brain tumor in adults with no curative therapy currently available
We analyzed whether inhibition of PIM1 kinase results in an altered expression of candidate stem cell markers (CD44, CD133, Nestin), as well as of the microglia (SPARC) and astrocytic marker protein (GFAP) in the human adherent GBM cell lines LN-18 and U-87 MG on the messenger ribonucleic acid (mRNA) level
To evaluate the impact of PIM1 inhibition on GBM stem cell features, we examined the expression of CD133, since several studies have demonstrated a close correlation between the expression of the stem cell marker CD133, chemoresistance and GBM survival [37,46,47]
Summary
Glioblastoma (GBM) represents the most common brain tumor in adults with no curative therapy currently available. It is assumed that successful treatment of GBM can only be achieved by targeting these highly tumorigenic, pro-mitogenic, pro-angiogenic and therapy-resistant GSCs [3,4]. The regulation of the molecular and biological properties of GSCs has not been well understood and remains elusive. Both natural and synthetic compounds have been evaluated for their potential to modify the behavior of GBM cells and GSCs, for instance, cannabinoids, resveratrol crocetin, the botanical drug PBI-05204, EGFR inhibitors, the PI3K/AKT small-molecule inhibitor A-443654, and many others [5,6,7,8]. The clinical impact of their therapeutic use on patient prognosis is not clear, many of their modes of action are known
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