CRM1/XPO1 is associated with clinical outcome in glioma and represents a therapeutic target by perturbing multiple core pathways

Abstract

Abstract Background Malignant gliomas are associated with a high mortality rate, and effective treatment options are limited. Thus, the development of novel targeted treatments to battle this deadly disease is imperative. Methods In this study, we investigated the in vitro effects of the novel reversible chromosomal region maintenance 1 (CRM1) inhibitor S109 on cell proliferation in human gliomas. S109 was also evaluated in an intracranial glioblastoma xenograft model. Results We found that high expression of CRM1 in glioma is a predictor of short overall survival and poor patient outcome. Our data demonstrate that S109 significantly inhibits the proliferation of human glioma cells by inducing cell cycle arrest at the G1 phase. Notably, we observed that high-grade glioma cells are more sensitive to S109 treatment compared with low-grade glioma cells. In an intracranial mouse model, S109 significantly prolonged the survival of tumor-bearing animals without causing any obvious toxicity. Mechanistically, S109 treatment simultaneously perturbed the three core pathways (the RTK/AKT/Foxos signaling pathway and the p53 and Rb1 tumor-suppressor pathways) implicated in human glioma cells by promoting the nuclear retention of multiple tumor-suppressor proteins. Conclusions Taken together, our study highlights the potential role of CRM1 as an attractive molecular target for the treatment of human glioma and indicates that CRM1 inhibition by S109 might represent a novel treatment approach.

Keywords

• Glioma
• CRM1 inhibitor
• S109
• Proliferation
• Cell cycle