Abstract
DNA replication is initiated with the recognition of the starting point of multiple replication forks by the origin recognition complex and activation of the minichromosome maintenance complex 10 (MCM10). Subsequently, DNA helicase, consisting of the MCM protein subunits MCM2-7, unwinds double-stranded DNA and DNA synthesis begins. In previous studies, replication factors have been used as clinical targets in cancer therapy. The results showed that MCM2 could be a proliferation marker for numerous types of malignant cancer. We analyzed samples obtained from patients with neuroblastoma, revealing that higher levels of MCM2 and MCM10 mRNA were associated with poor survival rate. Furthermore, we combined the results of the perturbation-induced reversal effects on the expression levels of MCM2 and MCM10 and the sensitivity correlation between perturbations and MCM2 and MCM10 from the Cancer Therapeutics Response Portal database. Small molecule BI-2536, a polo-like kinase 1 (PLK-1) inhibitor, is a candidate for the inhibition of MCM2 and MCM10 expression. To test this hypothesis, we treated neuroblastoma cells with BI-2536. The results showed that the drug decreased cell viability and reduced the expression levels of MCM2 and MCM10. Functional analysis further revealed enrichments of gene sets involved in mitochondria, cell cycle, and DNA replication for BI-2536-perturbed transcriptome. We used cellular assays to demonstrate that BI-2536 promoted mitochondria fusion, G2/M arrest, and apoptosis. In summary, our findings provide a new strategy for neuroblastoma therapy with BI-2536.
Highlights
We first examined whether the expression of maintenance complex (MCM) genes correlated with the tumor stage based on the International Neuroblastoma Staging System (INSS) for neuroblastoma
We found that expression of several MCM genes, except for MCM9, positively correlated with advanced disease stage and was relatively lower in stage 4S neuroblastoma, which usually exhibits better prognosis compared with other stages (Figure 1A,B, Figures S1 and S2, Supplementary Materials)
At 24 h after BI-2536 treatment, the mitochondria of SK-N-BE(2)C and SK-N-AS cells fused and elongated, with an observed increase in perimeter and area (Figure 6). These fused and elongated, with an observed increase in perimeter and area (Figure 6). These results suggested that BI-2536-treated cells may experience stress; cells stop the results suggested that BI-2536-treated cells may experience stress; cells stop the proprocess of mitosis, and mitochondria fuse to produce more energy against BI-2536-induced cess of mitosis, and mitochondria fuse to produce more energy against BI-2536-induced cellular stress
Summary
Neuroblastoma is the third most common type of cancer in children, with an overall survival rate
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