Neuroblastoma is an embryonal
tumor accounting for approximately 15% of childhood
cancer deaths. There exists a clinical need to identify novel therapeutic targets, particularly for treatment-resistant forms of
neuroblastoma. Therefore, we investigated the role of the neuronal master regulator GSK3 in controlling
neuroblastoma cell fate. We identified novel GSK3-mediated regulation of MYC (c-MYC and MYCN)
mRNA levels, which may have implications for numerous MYC-driven
cancers. In addition, we showed that certain GSK3 inhibitors induced large-scale cell death in
neuroblastoma cells, primarily through activating apoptosis.
mRNA-seq of GSK3 inhibitor-treated cells was performed and subsequent pathway analysis revealed that multiple signaling pathways contributed to the loss of
neuroblastoma cell viability. The contribution of two of the signaling pathways highlighted by the
mRNA-seq analysis was functionally validated. Inhibition of the p53
tumor suppressor partly rescued the cell death phenotype, whereas activation of canonical Wnt signaling contributed to the loss of viability, in a p53-independent manner. Two GSK3 inhibitors (
BIO-acetoxime and LiCl) and one small-molecule Wnt agonist (Wnt Agonist 1) demonstrated therapeutic potential for
neuroblastoma treatment. These inhibitors reduced the viability of numerous
neuroblastoma cell lines, even those derived from high-risk MYCN-amplified metastatic
tumors, for which effective
therapeutics are currently lacking. Furthermore, although LiCl was lethal to
neuroblastoma cells, it did not reduce the viability of differentiated neurons. Taken together our data suggest that these small molecules may hold potential as effective therapeutic agents for the treatment of
neuroblastoma and other MYC-driven
cancers.