Journal
ONCOLOGY REPORTS
Volume 36, Issue 5, Pages 2633-2640Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/or.2016.5085
Keywords
medulloblastoma; MPS1; mitosis; NMS-P715; kinase
Categories
Funding
- Childhood Brain Tumor Foundation
- Department of Pediatrics
- University of Colorado School of Medicine
- NIH-NINDS [K08NS059790, RO1NS086956]
- Morgan Adams Foundation
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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.
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