MELK Inhibition Effectively Suppresses Growth of Glioblastoma and Cancer Stem-Like Cells by Blocking AKT and FOXM1 Pathways.

Xu Zhang,Yifeng Wang,Runqiu Wu,Jiefeng Yu,Huan Li,Xuejiao Liu,Jie Wang,Guanzheng Liu,Rutong Yu,Jun Liang

doi:10.3389/fonc.2020.608082

Abstract

Glioblastoma multiforme (GBM) is a devastating disease yet no effective drug treatment has been established to date. Glioblastoma stem-like cells (GSCs) are insensitive to treatment and may be one of the reasons for the relapse of GBM. Maternal embryonic leucine zipper kinase gene (MELK) plays an important role in the malignant proliferation and the maintenance of GSC stemness properties of GBM. However, the therapeutic effect of targeted inhibition of MELK on GBM remains unclear. This study analyzed the effect of a MELK oral inhibitor, OTSSP167, on GBM proliferation and the maintenance of GSC stemness. OTSSP167 significantly inhibited cell proliferation, colony formation, invasion, and migration of GBM. OTSSP167 treatment reduced the expression of cell cycle G2/M phase-related proteins, Cyclin B1 and Cdc2, while up-regulation the expression of p21 and subsequently induced cell cycle arrest at the G2/M phase. OTSSP167 effectively prolonged the survival of tumor-bearing mice and inhibited tumor cell growth in in vivo mouse models. It also reduced protein kinase B (AKT) phosphorylation levels by OTSSP167 treatment, thereby disrupting the proliferation and invasion of GBM cells. Furthermore, OTSSP167 inhibited the proliferation, neurosphere formation and self-renewal capacity of GSCs by reducing forkhead box M1 (FOXM1) phosphorylation and transcriptional activity. Interestingly, the inhibitory effect of OTSSP167 on the proliferation of GSCs was 4-fold more effective than GBM cells. In conclusion, MELK inhibition suppresses the growth of GBM and GSCs by double-blocking AKT and FOXM1 signals. Targeted inhibition of MELK may thus be potentially used as a novel treatment for GBM.

Highlights

Glioblastoma multiforme (GBM) is the most common brain cancer in adults and is associated with a high mortality rate and poor prognosis [1, 2]
To evaluate the effect of Maternal embryonic leucine zipper kinase gene (MELK) inhibitor, OTSSP167 on GBM cell growth, a Cell Counting Kit-8 (CCK-8) assay was performed to assess the viability of GBM cells after OTSSP167 treatment
We found that the levels of MELK in all GBM cell lines had no obvious differences (Supplementary Files, Figure S1), which is consistent with the similar sensitivity of OTSSP167 to different cell lines

Summary

Introduction

Glioblastoma multiforme (GBM) is the most common brain cancer in adults and is associated with a high mortality rate and poor prognosis [1, 2]. Surgery is the major treatment for GBM, which is combined with postoperative radiotherapy and chemotherapy. No effective targeted drug for GBM treatment is currently available, and the identification of new therapeutic strategies, targeted therapy such as small-molecule drugs, is imperative. Glioblastoma stem-like cells (GSCs), known as brain tumor stem cells or promoter cells, are a subpopulation of GBM [5]. It is considered to be the driving force for supporting GBM development, invasion, and anti-treatment, as well malignant recurrence [6]. The eradication or permanent blockage of GSCs helps eliminate the formation and recurrence of GBM, and targeting GSC is essential

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Discussion

Conclusion