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  4. Combinatorial targeting of MTHFD2 and PAICS in purine synthesis as a novel therapeutic strategy
 
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Combinatorial targeting of MTHFD2 and PAICS in purine synthesis as a novel therapeutic strategy

Journal
Cell Death and Disease
Journal Volume
10
Journal Issue
11
Pages
786
Date Issued
2019
Author(s)
Cheung, H. Y. C
CHIA-LANG HSU  
Tsuei, C.-Y.
Kuo, T.-T.
Huang, C.-T.
WEN-MING HSU  
Chung, Y.-H.
Wu, H.-Y.
Hsu, C.-C.
Huang, H.-C.
CHENG-CHIH HSU  
DOI
10.1038/s41419-019-2033-z
URI
https://www.scopus.com/inward/record.uri?eid=2-s2.0-85073630693&doi=10.1038%2fs41419-019-2033-z&partnerID=40&md5=0e670ea52e9155335313806fe8c5c197
https://scholars.lib.ntu.edu.tw/handle/123456789/582945
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. ? 2019, The Author(s).
SDGs

[SDGs]SDG3

Other Subjects
5 amino 4 imidazolecarboxamide riboside; anisomycin; carbon; folic acid; guanosine phosphate; inosine phosphate; methylenetetrahydrofolate dehydrogenase 2; mitochondrial enzyme; nucleotide; paics enzyme; purine; short hairpin RNA; transcription factor; transcription factor mycn; unclassified drug; carboxylyase; hydrolase; methylenetetrahydrofolate dehydrogenase; MTHFD2 protein, human; multifunctional enzyme; phosphoribosylaminoimidazole carboxylase; purine; purine derivative; transcriptome; Article; cell metabolism; down regulation; gene expression; gene expression profiling; human; human cell; in vitro study; neuroblastoma; nucleotide sequence; priority journal; purine metabolism; purine synthesis; Western blotting; biosynthesis; cell cycle; cell growth; gene knockdown; genetic transfection; genetics; metabolism; metabolomics; molecularly targeted therapy; neuroblastoma; pathology; physiology; tumor cell line; upregulation; Aminohydrolases; Carboxy-Lyases; Cell Cycle; Cell Growth Processes; Cell Line, Tumor; Gene Knockdown Techniques; Humans; Metabolomics; Methylenetetrahydrofolate Dehydrogenase (NADP); Molecular Targeted Therapy; Multifunctional Enzymes; Neuroblastoma; Purines; Transcriptome; Transfection; Up-Regulation
Publisher
Nature Publishing Group
Type
journal article

臺大位居世界頂尖大學之列,為永久珍藏及向國際展現本校豐碩的研究成果及學術能量,圖書館整合機構典藏(NTUR)與學術庫(AH)不同功能平台,成為臺大學術典藏NTU scholars。期能整合研究能量、促進交流合作、保存學術產出、推廣研究成果。

To permanently archive and promote researcher profiles and scholarly works, Library integrates the services of “NTU Repository” with “Academic Hub” to form NTU Scholars.

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開放取用是從使用者角度提升資訊取用性的社會運動,應用在學術研究上是透過將研究著作公開供使用者自由取閱,以促進學術傳播及因應期刊訂購費用逐年攀升。同時可加速研究發展、提升研究影響力,NTU Scholars即為本校的開放取用典藏(OA Archive)平台。(點選深入了解OA)

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