Glycogen Synthase Kinase 3β Sustains Invasion of Glioblastoma via the Focal Adhesion Kinase, Rac1, and c-Jun N-Terminal Kinase-Mediated Pathway

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-3b (GSK3b), implicated in various diseases, including cancer. We previously reported that inhibition of GSK3b compromises the survival and proliferation of glioblastoma cells, induces their apoptosis, and sensitizes them to temozolomide and radiation. Here, we explore whether GSK3b also contributes to the highly invasive nature of glioblastoma. The effects of GSK3b 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 GSK3b 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 GSK3b 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. Mol Cancer Ther; 14(2); 564-74. Ó2014 AACR.

Upregulation of miR-501-5p activates the wnt/β-catenin signaling pathway and enhances stem cell-like phenotype in gastric cancer

“…For example, Tang et al found that loss of GSK-3β expression activated β-Catenin to upregulate the expression of miR-183-96-182 cluster, leading to proliferation and migration of gastric cancer [32]. In contrast, inhibition of GSK3β compromises the survival, proliferation and invasion of glioblastoma cells [33]. Herein, we found that miR-501-5p repressed GSK3β to activate Wnt/β-Catenin pathway and enhance gastric cancer stem cell phenotype, further suggesting a tumor-repressive role of GSK3β in gastric cancer.…”

MicroRNA-101 reverses temozolomide resistance by inhibition of GSK3β in glioblastoma

“…For example, Miyashita et al showed that GSK3β could promote the survival and proliferation of GBM cells and inhibit apoptosis through p53 and/or Rb-mediated pathways [21]. Chikano et al reported that GSK3β enhances invasion of GBM via the focal adhesion kinase, Rac1, and JNK pathway [50]. A recent study revealed that GSK3β could inhibit glioma progression via regulation of mTOR/p70S6K1 signaling pathway [51].…”

KLRC3, a Natural Killer receptor gene, is a key factor involved in glioblastoma tumourigenesis and aggressiveness

“…The decrease in DAP12 expression level in shKLRC3 cells associated with the significant decrease in the GSK3β protein strongly supports the hypothesis of a link between KLRC3 and DAP12 in the regulation of the glioblastoma aggressiveness, particularly in the radioresistance phenotype. GSK3β has been linked to glioma invasion ability 26 and its inhibition leads to an increase in glioma sensitivity to Temozolomide 27 and to radiotherapy 28. It has been also demonstrated that inhibition of GSK3β in GSC isolated from GBM patient samples attenuates cell proliferation, suggesting GSK3β as a potential therapeutical target in GSC 29.…”