Alimova Irina, Ng June, Harris Peter, Birks Diane, Donson Andrew, Taylor Michael D, Foreman Nicholas K, Venkataraman Sujatha, Vibhakar Rajeev
Department of Pediatrics, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA.
Oncol Rep. 2016 Nov;36(5):2633-2640. doi: 10.3892/or.2016.5085. Epub 2016 Sep 12.
Medulloblastoma is the most common type of malignant brain tumor that affects children. Although recent advances in chemotherapy and radiation have improved outcomes, high-risk patients perform poorly with significant morbidity. Gene expression profiling has revealed that monopolar spindle 1 (MPS1) (TTK1) is highly expressed in medulloblastoma patient samples compared to that noted in normal cerebellum. MPS1 is a key regulator of the spindle assembly checkpoint (SAC), a mitotic mechanism specifically required for proper chromosomal alignment and segregation. The SAC can be activated in aneuploid cancer cells and MPS1 is overexpressed in many types of cancers. A previous study has demonstrated the effectiveness of inhibiting MPS1 with small-molecule inhibitors, but the role of MPS1 in medulloblastoma is unknown. In the present study, we demonstrated that MPS1 inhibition by shRNA or with a small-molecule drug, NMS-P715, resulted in decreased cell growth, inhibition of clonogenic potential and induction of apoptosis in cells belonging to both the Shh and group 3 medulloblastoma genomic signature. These findings highlight MPS1 as a rational therapeutic target for medulloblastoma.
髓母细胞瘤是影响儿童的最常见的恶性脑肿瘤类型。尽管化疗和放疗方面的最新进展改善了治疗结果，但高危患者的预后仍然很差，且发病率很高。基因表达谱分析显示，与正常小脑相比，单极纺锤体1（MPS1）（TTK1）在髓母细胞瘤患者样本中高度表达。MPS1是纺锤体组装检查点（SAC）的关键调节因子，SAC是一种有丝分裂机制，是正确的染色体排列和分离所特别需要的。SAC可在非整倍体癌细胞中被激活，且MPS1在多种癌症类型中过表达。先前的一项研究已证明用小分子抑制剂抑制MPS1的有效性，但MPS1在髓母细胞瘤中的作用尚不清楚。在本研究中，我们证明，通过短发夹RNA（shRNA）或小分子药物NMS-P715抑制MPS1，会导致属于Shh和3组髓母细胞瘤基因组特征的细胞的生长减少、克隆形成潜力受到抑制以及细胞凋亡的诱导。这些发现突出了MPS1作为髓母细胞瘤合理治疗靶点的地位。
