Signaling Pathways in Glioblastoma Cancer Stem Cells: A Role of Stat3 as a Potential Therapeutic Target

Glioblastoma cancer stem cells (GCSCs) play an important role in proliferation, invasion, progression, immune evasion, and resistance to radiation in glioblastoma. Their signaling pathways including receptor tyrosine kinase, Akt, MARK, Wnt, Notch, Hedgehog, and JAK/STAT pathways are complicated, but STAT-3 is a convergence point in several important signaling pathways and contributes to the tumor progression by promoting cell proliferation, cell cycle progression, the inhibition of apoptosis, and tissue invasion. Therefore, STAT- 3 is a candidate of therapeutic target of GCSCs. STAT3 is activated through tyrosine phosphorylation by various cytokines and growth factors. STAT-3 is tyrosine phosphorylated by three types of kinases such as receptor tyrosine kinases, JAK family members, and oncogenic kinases including Src and Bcl- Alb. Tyrosine phosphorylated STAT-3 dimerizes and translocates to the nucleus. Active STAT-3 dimers bind to consequences in the promoters of genes such as Bcl-2, Bcl-xL, Mcl-1, and cyclin D1. After induction of target gene expression, multiple STAT-3-endogenous negative regulators such as SOCS3, VHL, and PIAS3 attenuate STAT-3 signaling, and similarly STAT-3 exogenous negative regulators such as pharmacologic JAK inhibitors, dobesilate, and decoy oligonucleotides attenuate STAT-3 activity. In GCSCs, STAT-3 plays a role as a molecular hub in several important signaling pathways that control proliferation, cell cycle progression, anti-apoptosis, invasion, angiogenesis and immune evasion. Therefore, STAT-3 has great potential as a therapeutic target.