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Potential therapeutic effect of glycogen synthase kinase 3beta inhibition against human glioblastoma
Katsuyoshi Miyashita1, Kazuyuki Kawakami, Mitsutoshi Nakada
1Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa, Japan.
Purpose:
Glioblastoma represents the malignant brain tumor that is most refractory to treatment and in which the identification of molecular target(s) is urgently required. We investigated the expression, activity, and putative pathologic role of glycogen synthase kinase 3beta (GSK3beta), an emerging therapeutic target for neurodegenerative diseases, in human glioblastoma.
Experimental Design:
The active fraction of GSK3beta that is phosphorylated at the tyrosine 216 residue (pGSK3betaY216) was identified in glioblastoma cell lines. GSK3beta activity for phosphorylating its substrate was detected in these cells by nonradioisotopic in vitro kinase assay.
Results:
Higher expression levels of GSK3beta and pGSK3betaY216 were frequently detected in glioblastomas compared with nonneoplastic brain tissues. Inhibition of GSK3beta activity by escalating doses of a small-molecule inhibitor (AR-A014418) or inhibition of its expression by RNA interference induced the apoptosis and attenuated the survival and proliferation of glioblastoma cells in vitro. Inhibition of GSK3beta was associated with increased expression of p53 and p21 in glioblastoma cells with wild-type p53 and with decreased Rb phosphorylation and expression of cyclin-dependent kinase 6 in all glioblastoma cell lines. Administration of AR-A014418 at a low dose significantly sensitized glioblastoma cells to temozolomide and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea, chemotherapeutic agents used in the clinical setting, as well as to ionizing radiation.
Conclusion:
These results indicate that GSK3beta exerts a pathologic role by promoting the survival and proliferation of glioblastoma cells and by protecting them from apoptosis via the inactivation of p53- and/or Rb-mediated pathways. Consequently, we propose that GSK3beta provides a potential therapeutic target in glioblastoma.
Insights
Glycogen synthase kinase 3beta (GSK3beta) promotes glioblastoma growth and survival. Inhibiting GSK3beta induces apoptosis and sensitizes cancer cells to chemotherapy and radiation, suggesting it is a potential therapeutic target.
Area of Science:
- Neuro-oncology
- Molecular biology
- Cancer research
Background:
- Glioblastoma is a highly aggressive brain tumor with limited treatment options.
- Identifying novel molecular targets is crucial for effective glioblastoma therapy.
- Glycogen synthase kinase 3beta (GSK3beta) is implicated in neurodegenerative diseases and is an emerging therapeutic target.
Purpose of the Study:
- To investigate the expression, activity, and role of GSK3beta in human glioblastoma.
- To determine if GSK3beta is a viable therapeutic target for glioblastoma treatment.
Main Methods:
- Analysis of GSK3beta and phosphorylated GSK3beta (pGSK3betaY216) expression in glioblastoma tissues.
- In vitro assessment of GSK3beta activity using kinase assays.
- Treatment of glioblastoma cell lines with GSK3beta inhibitors (AR-A014418) and RNA interference.
- Evaluation of apoptosis, survival, proliferation, p53, p21, Rb phosphorylation, and cyclin-dependent kinase 6 expression.
- Assessment of drug and radiation sensitivity following GSK3beta inhibition.
Main Results:
- Elevated GSK3beta and pGSK3betaY216 levels were observed in glioblastomas compared to normal brain tissue.
- GSK3beta inhibition via AR-A014418 or RNA interference induced apoptosis and reduced glioblastoma cell survival and proliferation.
- GSK3beta inhibition modulated p53, p21, Rb phosphorylation, and cyclin-dependent kinase 6 expression.
- GSK3beta inhibition sensitized glioblastoma cells to temozolomide, nitrosourea, and ionizing radiation.
Conclusions:
- GSK3beta plays a pathological role in glioblastoma by promoting cell survival and proliferation.
- GSK3beta contributes to glioblastoma resistance to apoptosis through p53 and Rb pathway inactivation.
- GSK3beta represents a promising therapeutic target for glioblastoma treatment.