Differential effects of glycogen synthase kinase 3 inhibitors on migration in glioblastoma cell lines
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Glioblastoma multiforme (GBM) represents the deadliest brain cancer pathology. Current therapeutic treatment focuses on surgical resection of tumors, followed by adjuvant radiation and/or chemotherapy. The invasive nature of GBM however limits the effectiveness of such therapy. Drug development for GBM has centered on attempts to manage this infiltrative capacity. One avenue of such development focuses on aberrant cellular signaling pathways characteristic of malignancies. This study sought to understand the mechanism by which glycogen synthase kinase 3 (GSK-3) inhibitors differentially regulate GBM migration. Measurement of in vitro cellular migration has traditionally utilized Boyden chamber (transwell) assays and collagen migration assays. Administration of known GSK-3 inhibitors demonstrate a differential effect, whereby migration is inhibited in transwell assays, but maintained in the collagen assay. Cell aggregates from 4 different GBM cell lines were utilized in comparison of GSK-3 inhibitor effects in both the transwell and collagen assays. Contrary to previous findings, GSK-3 inhibitors demonstrated limited effect in reducing migration in the transwell assay, while demonstrating modest effects in the collagen assay. A mechanistic understanding of GSK-3 inhibitor function remains elusive. Previous studies have demonstrated GSK-3 effects on various cytoskeletal proteins, including the WAVE-2 complex, vital for cytoskeletal stability. Administration of GSK-3 inhibitors had previously led to a downregulation of WAVE2 levels. After administration of known GSK-3 inhibitors, this study failed to reproduce previous differences in total WAVE2 protein levels compared to control untreated samples. This evidence indicates a different mode of cytoskeletal regulation must be driving GSK-3 inhibition’s effect on GBM migration. GSK-3 inhibitors represent one promising class of chemotherapeutic agents for treatment of GBM. This study corroborated previous findings about the effect of classical GSK-3 inhibitors (BIO, CHI99021) in reducing GBM migration. Further investigation is necessary to isolate the specific cellular mechanisms responsible for GSK-3’s effects. With rapid development of other therapeutic strategies, GSK-3 inhibitors present one class of drugs available to clinicians for effective therapeutic management of GBM.