PIM1 Inhibition Affects Glioblastoma Stem Cell Behavior and Kills Glioblastoma Stem-like Cells
Carolin Seifert1,2, Ellen Balz1,2, Susann Herzog1
1Department of Pharmacology, University Medicine Greifswald, 17489 Greifswald, Germany.
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.
Insights
Targeting PIM1 kinase inhibits glioblastoma stem cell growth and survival. PIM1 inhibition reduces stem cell markers and decreases glioblastoma cell viability, offering a potential new therapy.
Area of Science:
- Oncology
- Cancer Stem Cell Biology
- Molecular Therapeutics
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with high recurrence rates.
- Glioma stem cells (GSCs) are implicated in GBM progression and treatment resistance.
- The role of PIM1 kinase in GSCs remains largely unexplored.
Purpose of the Study:
- To investigate the role of PIM1 kinase in glioblastoma stem cell behavior.
- To evaluate the therapeutic potential of PIM1 inhibition in GSCs.
Main Methods:
- Assessed PIM1 inhibition effects on stem cell markers (CD133, Nestin, CD44, GFAP) in GBM cell lines (LN-18, U-87 MG).
- Utilized neurospheres as a model for glioblastoma stem-like cells.
- Treated neurospheres with PIM1 inhibitors (TCS PIM1-1, Quercetagetin, LY294002) and measured cell viability, DNA synthesis, caspase 3 activity, PCNA expression, and neurosphere formation.
Main Results:
- PIM1 inhibition downregulated CD133 and Nestin while upregulating CD44 and GFAP in GBM cells.
- PIM1 expression was elevated in glioblastoma stem-like cell neurospheres.
- PIM1 inhibition in neurospheres reduced cell viability, DNA synthesis, and neurosphere formation, while increasing caspase 3 activity and decreasing PCNA expression.
Conclusions:
- PIM1 kinase plays a significant role in regulating glioblastoma stem cell behavior.
- Inhibition of PIM1 effectively reduces glioblastoma stem-like cell viability and proliferation.
- Targeting PIM1 represents a promising therapeutic strategy against glioblastoma.
