Quantitative Proteomics of Th-MYCN Transgenic Mice Reveals Aurora Kinase Inhibitor Altered Metabolic Pathways and Enhanced ACADM to Suppress Neuroblastoma Progression
Journal
Journal of Proteome Research
Journal Volume
18
Journal Issue
11
Pages
3850-3866
Date Issued
2019
Author(s)
Hsieh, Chiao-Hui
Cheung, Chantal Hoi Yin
Liu, Yen-Lin
Hou, Chun-Li
Huang, Chen-Tsung
Yang, Tsai-Shan
Chen, Sung-Fang
Huang, Hsuan-Cheng
Juan, Hsueh-Fen
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. © 2019 American Chemical Society.
Subjects
aurora kinases
metabolic pathway
MYCN
neuroblastoma
quantitative proteomics
tozasertib
transgenic mice
SDGs
Other Subjects
acadm protein; aurora A kinase; aurora B kinase; aurora kinase; aurora kinase inhibitor; flavoprotein; mitochondrial enzyme; oncoprotein; tozasertib; unclassified drug; acyl coenzyme A dehydrogenase; aurora kinase; N Myc proto oncogene protein; piperazine derivative; protein kinase inhibitor; tozasertib; animal experiment; animal model; animal tissue; Article; cancer inhibition; cancer survival; carbohydrate metabolism; cell cycle arrest; cell migration; cell proliferation; controlled study; event free survival; fatty acid metabolism; fatty acid oxidation; gene amplification; gene expression level; human; human cell; metabolism; mouse; neuroblastoma; neuroblastoma cell line; nonhuman; oncogene c myb; overall survival; priority journal; proteomics; quantitative analysis; transcriptomics; transgenic mouse; tumor invasion; 129 mouse; animal; disease exacerbation; drug effect; gene expression profiling; gene expression regulation; genetics; metabolism; neuroblastoma; procedures; proteomics; survival analysis; tumor cell line; Acyl-CoA Dehydrogenase; Animals; Aurora Kinases; Cell Line, Tumor; Cell Proliferation; Disease Progression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Metabolic Networks and Pathways; Mice, 129 Strain; Mice, Transgenic; N-Myc Proto-Oncogene Protein; Neuroblastoma; Piperazines; Protein Kinase Inhibitors; Proteomics; Survival Analysis
Publisher
American Chemical Society
Type
journal article