INSM2 promotes the development of neuroblastoma by regulating lipid metabolism
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA828593 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18840487_1.fastq.gz | Fastqsanger.gz | |||
| SRR18840487_2.fastq.gz | Fastqsanger.gz | |||
| SRR18840488_1.fastq.gz | Fastqsanger.gz | |||
| SRR18840488_2.fastq.gz | Fastqsanger.gz | |||
| SRR18840489_1.fastq.gz | Fastqsanger.gz |
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Project description:Neuroblastoma is the most common heterogeneous solid tumor in childhood, with limited treatments available for high-risk patients. Previous studies have shown that Dihydroorotate dehydrogenase (DHODH) plays an essential role in the de novo synthesis of pyrimidine and have identified it as a potential therapeutic target in cancer. Our previous studies have shown that the higher expression of DHODH is associated with the worst survival of neuroblastoma patients. Through knockdown experiments, we validated that reducing DHODH expression in neuroblastoma cells leads to a decrease in cell viability. Subsequently, we harnessed virtual screening software to repurpose drugs, targeting DHODH as potential neuroblastoma therapeutics. We conducted molecular docking simulations with a database of 2702 FDA-approved drugs on DHODH and identified a number of drugs that demonstrated high affinity for DHODH. Among these drugs, we found Regorafenib, a multi-kinase inhibitor, effectively inhibited neuroblastoma cell proliferation and was more efficient than leflunomide, an FDA-approved DHODH inhibitor. To determine whether Regorafenib is a novel DHODH inhibitor, we employed thermal shift and enzyme fluorescence assays. These assays revealed that Regorafenib not only enhanced binding stability but also reduced the enzymatic activity of DHODH. Since Regorafenib is a multi-kinase inhibitor, we confirm changes in downstream proteins by comparison with shDHODH to determine whether these alterations result from targeting DHODH. To further investigate the molecular mechanism of Regorafenib in targeting DHODH, we conducted a proteome analysis using tandem mass tag (TMT) labeling. This involved comparing samples treated with Regorafenib to those with DHODH knockdown. Using Liquid Chromatograph-mass spectrometry/ mass spectrometry (LC-MS/MS), a total of 4471 proteins and 31518 peptides were identified. Furthermore, we identified 377 differentially expressed proteins in the shDHODH sample and 225 in the Regorafenib treatment sample. We performed gene ontology (GO) enrichment analysis on these two sets of samples. The results of the GO enrichment analysis indicate that these proteins are associated with lipid metabolism in terms of biological functions. Through literature searches, we found that the results from proteomics analysis and Western blot validation both show that the commonly differentially expressed proteins are related to the mevalonate pathway. This pathway, when affected, influences ferroptosis. Additionally, we discovered a relationship between DHODH inhibition and lipid droplet production. In summary, previous studies have shown a connection between DHODH and ferroptosis. However, we identified a new mechanism where DHODH inhibition induces ferroptosis by affecting the mevalonate pathway. Therefore, our findings underscore the potential of using Regorafenib to target DHODH, proposing a novel and promising therapeutic strategy for high-risk neuroblastoma.
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