Back to Search
Start Over
Combinatorial targeting of MTHFD2 and PAICS in purine synthesis as a novel therapeutic strategy.
- Source :
-
Cell death & disease [Cell Death Dis] 2019 Oct 17; Vol. 10 (11), pp. 786. Date of Electronic Publication: 2019 Oct 17. - Publication Year :
- 2019
-
Abstract
- MYCN-amplified (MNA) neuroblastoma is an aggressive neural crest-derived pediatric cancer. However, MYCN is indispensable for development and transcriptionally regulates extensive network of genes. Integrating anti-MYCN ChIP-seq and gene expression profiles of neuroblastoma patients revealed the metabolic enzymes, MTHFD2 and PAICS, required for one-carbon metabolism and purine biosynthesis were concomitantly upregulated, which were more susceptible to metastatic neuroblastoma. Moreover, we found that MYCN mediated the folate cycle via MTHFD2, which contributed one-carbon unit to enhance purine synthesis, and further regulated nucleotide production by PAICS in response to cancer progression. Dual knockdown of the MYCN-targeted gene pair, MTHFD2 and PAICS, in MNA neuroblastoma cells synergically reduced cell proliferation, colony formation, migration ability, and DNA synthesis. By systematically screening the compound perturbagens, the gene expression levels of MTHFD2 and PAICS were specifically suppressed by anisomycin and apicidin across cell lines, and our co-treatment results also displayed synergistic inhibition of MNA neuroblastoma cell proliferation. Collectively, targeting a combination of MYCN-targeted genes that interrupts the interconnection of metabolic pathways may overcome drug toxicity and improve the efficacy of current therapeutic agents in MNA neuroblastoma.
- Subjects :
- Aminohydrolases genetics
Carboxy-Lyases genetics
Cell Cycle physiology
Cell Growth Processes
Cell Line, Tumor
Gene Knockdown Techniques
Humans
Metabolomics
Methylenetetrahydrofolate Dehydrogenase (NADP) genetics
Molecular Targeted Therapy
Multifunctional Enzymes genetics
Neuroblastoma genetics
Neuroblastoma metabolism
Neuroblastoma pathology
Neuroblastoma therapy
Transcriptome
Transfection
Up-Regulation
Aminohydrolases metabolism
Carboxy-Lyases metabolism
Methylenetetrahydrofolate Dehydrogenase (NADP) metabolism
Multifunctional Enzymes metabolism
Purines biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 10
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 31624245
- Full Text :
- https://doi.org/10.1038/s41419-019-2033-z