Abstract
Neuroblastoma is the most common paediatric cancer type. Patients diagnosed with high-risk neuroblastoma have poor prognosis and occasionally tumours relapse. As a result, novel treatment strategies are needed for relapse and refractory neuroblastoma patients. Here, we found that high expression of Mps1 kinase (mitotic kinase Monopolar Spindle 1) was associated with relapse-free neuroblastoma patient outcomes and poor overall survival. Silencing and inhibition of Mps1 in neuroblastoma or PDX-derived cells promoted cell apoptosis via the caspase-dependent mitochondrial apoptotic pathway. The mechanism of cell death upon Mps1 inhibition was dependent on the polyploidization/aneuploidization of the cells before undergoing mitotic catastrophe. Furthermore, tumour growth retardation was confirmed in a xenograft mouse model after Mps1-inhibitor treatment. Altogether, these results suggest that Mps1 expression and inhibition can be considered as a novel prognostic marker as well as a therapeutic strategy for the treatment of high-risk neuroblastoma patients.
Highlights
Neuroblastoma is the most common extra-cranial solid tumour of childhood[1,2] causing approximately 10% of all childhood cancer-related deaths[3,4]
Analysis of neuroblastoma patients showed that Mps[1] expression was significantly higher in MYCN amplified neuroblastoma compared to non-amplified (Fig. 1E and Fig. S1A–C)
Autophagosome formation was shown to be upregulated upon Mps1 depletion[35], we investigated autophagy in SK-N-Be2c neuroblastoma cells treated with Reversine or Mps-BAY2a
Summary
Neuroblastoma is the most common extra-cranial solid tumour of childhood[1,2] causing approximately 10% of all childhood cancer-related deaths[3,4]. Neuroblastoma is a very heterogeneous tumour compared to other cancers. It can regress spontaneously, in certain cases, can undergo treatment r esistance[5,6]. Identification of the high-risk group is important for the development of personalised medicine for neuroblastoma patients with poor prognosis. High-risk neuroblastoma represent 40% of all diagnosed cases, and these patients have poor prognosis harbouring tumour relapse and chemoresistance, and only 50% will attain long-term survival[9,10]. In non-MYCN high-risk neuroblastoma, point mutations in TP53 and Anaplastic Lymphoma Kinase (ALK) gene mutation have been observed[12] in less than 10% of neuroblastomas[13]. Reversine (2-(4-morpholinoanilino)-6-cyclohexylaminopurine), is the most common Mps[1] inhibitor used in cell biology research. Mps-BAY2a showed a restricted inhibitory effect on a panel of 220 human kinases compared to Reversine[25]
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