Multifarious functions of butyrylcholinesterase in neuroblastoma: Impact of bche deletion on the neuroblastoma growth in vitro and in vivo

Janina Baranowska-Kortylewicz, Zbigniew P. Kortylewicz, Erin M. McIntyre, John G. Sharp, Don W. Coulter

Research output: Contribution to journalArticlepeer-review

Abstract

The physiological functions of butyrylcholinesterase (BChE) and its role in malignancy remain unexplained. Our studies in children newly diagnosed with neuroblastoma indicated that BChE expressions is proportional to MYCN amplification suggesting that pathogenesis of high-risk disease may be related to the persistent expression of abnormally high levels of tumor-associated BChE. BChE-deficient neuroblastoma cells (KO [knockout]) were produced from MYCN-amplified BE(2)-C cells (WT [wild-type]) by the CRISPR-Cas9 targeted disruption of the BCHE locus. KO cells have no detectable BChE activity. The compensatory acetylcholinesterase activity was not detected. The average population doubling time of KO cells is 47.0 ± 2.4 hours, > 2× longer than WT cells. Reduced proliferation rates of KO cells were accompanied by the loss of N-Myc protein and a significant deactivation of tyrosine kinase receptors associated with the aggressive neuroblastoma phenotype including Ros1, TrkB, and Ltk. Tumorigenicity of WT and KO cells in male mice was essentially identical. In contrast, KO xenografts in female mice were very small (0.37 ± 0.10 g), ~3× smaller compared with WT xenografts (1.11 ± 0.30 g). Unexpectedly, KO xenografts produced changes in plasma BChE similarly to WT tumors but lesser in magnitude. The disruption of BCHE locus in MYCN-amplified neuroblastoma cells decelerates proliferation and produces neuroblastoma cells that are less aggressive in female mice.

Original languageEnglish (US)
JournalJournal of Pediatric Hematology/Oncology
DOIs
StateAccepted/In press - 2021
Externally publishedYes

Keywords

  • BCHE-deleted
  • Butyrylcholinesterase
  • Loss of N-Myc
  • Neuroblastoma
  • Pathogenesis

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

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