STEM-43. GSK3β PROMOTES THE BMX-MEDIATED STAT3 ACTIVATION TO MAINTAIN GLIOBLASTOMA STEM CELLS

Glioblastoma (GBM) is the most lethal brain cancer containing highly tumorigenic glioma stem cells (GSCs). As GSCs contribute to malignant behaviors including tumor angiogenesis, cancer invasion, therapeutic resistance and tumor recurrence, targeting GSCs may significantly improve GBM treatment. Here we demonstrate that the glycogen synthase kinase 3β (GSK3β) promotes the BMX-mediated STAT3 signaling to maintain GSCs and thus targeting GSK3β impairs GBM tumor growth. GSK3β is preferentially activated in GSCs relative to matched non-stem tumor cells (NSTCs) and neural progenitor cells (NPCs). Functional inhibition of GSK3β by its inhibitors or shRNA reduced activating phosphorylation of BMX kinase and STAT3 in GSCs but not in NPCs that express little BMX. Disrupting GSK3β inhibited GSC tumorsphere formation and induced cell death in GSCs but showed little effect on NPCs. Importantly, disruption of GSK3β potently suppressed GSC-driven tumor growth in vivo. Ectopic expression of a constitutively active STAT3 (STAT3-C) rescued the effects caused by GSK3β disruption, supporting that GSK3β mediates through STAT3 activation to maintain the GSC phenotype. Collectively, these data indicate that GSK3β is a potential therapeutic target of GSCs. Thus, pharmacological inhibition of GSK3β may potently disrupt GSCs to overcome therapeutic resistance and improve GBM treatment.