Downregulation of Gankyrin/PSMD10 affects cancer cell growth and proliferation in glioblastoma: in vitro and in vivo study

The oncoprotein Gankyrin/PSMD10 is upregulated in various cancers, including glioblastoma multiforme (GBM), the most difficult tumor to treat. The heterogeneity of this type of tumor requires a multi-targeted approach to overcome radio- and chemoresistance. Here we aim to investigate the effects of Gankyrin inhibition on glioma cell proliferation and its impact on sensitivity to chemotherapy both in vitro and in vivo . We have employed the RNA interference approach as a valuable tool to downregulate the expression of target genes. Small interfering RNA (siRNA) were formulated into lipid nanoparticles (LNP) to facilitate delivery and overcome challenges, including RNase activity. We demonstrate that knockdown of Gankyrin promotes cell growth arrest of murine (GL261, CT-2А) and human (U87, GBM23, GBM24) glioma cells and induces the generation of reactive oxygen species and apoptosis. Importantly, Gankyrin inhibition enhances the therapeutic effect of temozolomide in murine glioma cell lines and decreases the IC50 of doxorubicin and cisplatin for U87 and GL261 cells. The therapeutic potential of Gankyrin inhibition was shown in patient-derived glioblastoma stem cells, which are responsible for tumor initiation and resistance to therapy. We showed that downregulation of Gankyrin led to decreased cell proliferation in vitro and improved survival in xenograft glioma model mice. Our results suggest that harnessing siRNA against Gankyrin may serve as a novel therapeutic strategy for glioblastoma therapy in a multi-drug approach and address challenges in current treatment by sensitizing glioma cells to chemotherapy.

Highlights

• siRNA-mediated knockdown of Gankyrin reduced cell proliferation of murine and human glioma cells, induced ROS generation and promoted apoptosis.

• Inhibition of Gankyrin increased the therapeutic effect of temozolomide in resistant CT- 2A glioma cells and decreased the IC50 concentration of doxorubicin and cisplatin in U87 and GL261 cells.

• Downregulation of Gankyrin inhibited the growth of patient-derived glioma stem cells and increased the survival of NOD/SCID xenograft glioma model mice