Abstract
The failure of current treatment options for glioblastoma stems from their inability to control tumor cell proliferation and invasion. Biologically targeted therapies offer great hope and one promising target is glycogen synthase kinase-3β (GSK3β), implicated in various diseases, including cancer. We previously reported that inhibition of GSK3β compromises the survival and proliferation of glioblastoma cells, induces their apoptosis, and sensitizes them to temozolomide and radiation. Here, we explore whether GSK3β also contributes to the highly invasive nature of glioblastoma. The effects of GSK3β inhibition on migration and invasion of glioblastoma cells were examined by wound-healing and Transwell assays, as well as in a mouse model of glioblastoma. We also investigated changes in cellular microarchitectures, cytoskeletal components, and proteins responsible for cell motility and invasion. Inhibition of GSK3β attenuated the migration and invasion of glioblastoma cells in vitro and that of tumor cells in a mouse model of glioblastoma. These effects were associated with suppression of the molecular axis involving focal adhesion kinase, guanine nucleotide exchange factors/Rac1 and c-Jun N-terminal kinase. Changes in cellular phenotypes responsible for cell motility and invasion were also observed, including decreased formation of lamellipodia and invadopodium-like microstructures and alterations in the subcellular localization, and activity of Rac1 and F-actin. These changes coincided with decreased expression of matrix metalloproteinases. Our results confirm the potential of GSK3β as an attractive therapeutic target against glioblastoma invasion, thus highlighting a second role in this tumor type in addition to its involvement in chemo- and radioresistance.
Highlights
Glioblastoma is the most frequent and lethal type of malignant primary brain tumor[1]
The transwell assay showed that AR-A014418 and glycogen synthase kinase-3β (GSK3β)-RNA interference (RNAi) inhibited the migration of glioblastoma cells and their invasion of extracellular matrix (ECM) constituents (Figure 1B, C; Supplementary Figure S1)
Changes in cell migration phenotypes following GSK3β inhibition Amongst the different cellular microarchitectures involved in cell motility and invasion, we focused here on lamellipodia[28] because these structures were frequently observed in glioblastoma cells growing in non-confluent conditions (Figure 2, Supplementary Figure S2)
Summary
Glioblastoma is the most frequent and lethal type of malignant primary brain tumor[1]. Recent clinical trials using pharmacological inhibitors of epidermal growth factor receptor (EGFR) and HER2 and therapeutic antibodies against EGFR failed to show significant clinical benefit[4]. This is probably due to extensive heterogeneity at the cellular and molecular levels and the complex interplay between different oncogenic signaling pathways in tumor cells[5]. Clinical trials using the anti-angiogenic agent bevacizumab, a monoclonal antibody to vascular endothelial growth factor, demonstrated some improvement in progression-free survival in newly diagnosed and recurrent glioblastomas, but failed to show an overall survival benefit[4]. The effective targeting of biological mechanisms that facilitate tumor cell invasion will be crucial for the development of more successful treatment strategies[8]
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