Quantitative Proteomics of Th-MYCN Transgenic Mice Reveals Aurora Kinase Inhibitor Altered Metabolic Pathways and Enhanced ACADM to Suppress Neuroblastoma Progression

Chiao Hui Hsieh, Chantal Hoi Yin Cheung, Yen Lin Liu, Chun Li Hou, Chia Lang Hsu, Chen Tsung Huang, Tsai Shan Yang, Sung Fang Chen, Chiung Nien Chen, Wen Ming Hsu, Hsuan Cheng Huang, Hsueh Fen Juan

Research output: Contribution to journalArticlepeer-review

Abstract

Neuroblastoma is a neural crest-derived embryonal tumor and accounts for about 15% of all cancer deaths in children. MYCN amplification is associated with aggressive and advanced stage of high-risk neuroblastoma, which remains difficult to treat and exhibits poor survival under current multimodality treatment. Here, we analyzed the transcriptomic profiles of neuroblastoma patients and showed that aurora kinases lead to poor survival and had positive correlation with MYCN amplification and high-risk disease. Further, pan-aurora kinase inhibitor (tozasertib) treatment not only induces cell-cycle arrest and suppresses cell proliferation, migration, and invasion ability in MYCN-amplified (MNA) neuroblastoma cell lines, but also inhibits tumor growth and prolongs animal survival in Th-MYCN transgenic mice. Moreover, we performed quantitative proteomics and identified 150 differentially expressed proteins after tozasertib treatment in the Th-MYCN mouse model. The functional and network-based enrichment revealed that tozasertib alters metabolic processes and identified a mitochondrial flavoenzyme in fatty acid β-oxidation, ACADM, which is correlated with aurora kinases and neuroblastoma patient survival. Our findings indicate that the aurora kinase inhibitor could cause metabolic imbalance, possibly by disturbing carbohydrate and fatty acid metabolic pathways, and ACADM may be a potential target in MNA neuroblastoma.

Original languageEnglish
Pages (from-to)3850-3866
Number of pages17
JournalJournal of Proteome Research
Volume18
Issue number11
DOIs
Publication statusPublished - 2019 Nov 1

Keywords

  • MYCN
  • aurora kinases
  • metabolic pathway
  • neuroblastoma
  • quantitative proteomics
  • tozasertib
  • transgenic mice

ASJC Scopus subject areas

  • Biochemistry
  • Chemistry(all)

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