Zhang Xu, Wang Jie, Wang Yifeng, Liu Guanzheng, Li Huan, Yu Jiefeng, Wu Runqiu, Liang Jun, Yu Rutong, Liu Xuejiao
Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, China.
Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
Front Oncol. 2021 Jan 14;10:608082. doi: 10.3389/fonc.2020.608082. eCollection 2020.
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 () 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 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 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.
多形性胶质母细胞瘤（GBM）是一种毁灭性疾病，但迄今为止尚未建立有效的药物治疗方法。胶质母细胞瘤干细胞（GSCs）对治疗不敏感，可能是GBM复发的原因之一。母源胚胎亮氨酸拉链激酶基因（）在GBM的恶性增殖和GSC干性特性的维持中起重要作用。然而，靶向抑制对GBM的治疗效果仍不清楚。本研究分析了MELK口服抑制剂OTSSP167对GBM增殖和GSC干性维持的影响。OTSSP167显著抑制GBM的细胞增殖、集落形成、侵袭和迁移。OTSSP167处理降低了细胞周期G2/M期相关蛋白Cyclin B1和Cdc2的表达，同时上调了p21的表达，随后诱导细胞周期停滞在G2/M期。OTSSP167有效地延长了荷瘤小鼠的生存期，并在小鼠模型中抑制了肿瘤细胞的生长。通过OTSSP167处理还降低了蛋白激酶B（AKT）的磷酸化水平，从而破坏了GBM细胞的增殖和侵袭。此外，OTSSP167通过降低叉头框M1（FOXM1）的磷酸化和转录活性，抑制了GSCs的增殖、神经球形成和自我更新能力。有趣的是，OTSSP167对GSCs增殖的抑制作用比GBM细胞强4倍。总之，抑制MELK通过双重阻断AKT和FOXM1信号来抑制GBM和GSCs的生长。因此，靶向抑制MELK可能潜在地用作GBM的一种新的治疗方法。
