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

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.