Notch pathway activation induces neuroblastoma tumor cell growth arrest

Peter E. Zage, Riitta Nolo, Wendy Fang, John Stewart, Guillermo Garcia-Manero, Patrick A. Zweidler-Mckay

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Background: Notch pathway signaling has critical roles in differentiation, proliferation, and survival, and has oncogenic or tumor suppressor effects in a variety of malignancies. The goal of this study was to evaluate the effects of Notch activation on human neuroblastoma cells. Procedure: Quantitative RT-PCR, immunoblots, and immunohistochemistry were used to determine the expression of Notch receptors (Notch1-4), cleaved Notch1 (ICN1), and downstream targets (HES1-5) in human neuroblastoma cell lines and patient tumor samples. Notch pathway signaling was induced using intracellular Notch (ICN1-3) and HES gene constructs or direct culture on Notch ligands. Quantitative methylation-specific PCR was used to quantify methylation of the HES gene promoters, and the effects of treatment with decitabine were measured. Results: Neuroblastoma cells express varying levels of Notch receptors and low levels of HES genes at baseline. However, no endogenous activation of the Notch pathway was detected in neuroblastoma cell lines or patient tumor samples. Expression of activated Notch intracellular domains and HES gene products led to growth arrest. The HES2 and HES5 gene promoters were found to be heavily methylated in most neuroblastoma lines, and HES gene expression could be induced through treatment with decitabine. Conclusions: We report that neuroblastoma cell lines express multiple Notch receptors, which are inactive at baseline. Activation of the Notch pathway via ligand binding consistently resulted in growth arrest. HES gene expression appears to be regulated epigenetically and could be induced with decitabine. These findings support a tumor suppressor role for Notch signaling in neuroblastoma.

Original languageEnglish (US)
Pages (from-to)682-689
Number of pages8
JournalPediatric Blood and Cancer
Volume58
Issue number5
DOIs
StatePublished - May 2012

Keywords

  • HES
  • ICN
  • Neuroblastoma
  • Notch

ASJC Scopus subject areas

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

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