Contribution of Notch signaling activation to human glioblastoma multiforme

Masayuki Kanamori, Tomohiro Kawaguchi, Janice M. Nigro, Burt G. Feuerstein, Mitchel S. Berger, Lucio Miele, Russell O. Pieper

Research output: Contribution to journalArticle

141 Scopus citations

Abstract

Object. Because activation of Notch receptors has been suggested to be critical for Ras-mediated transformation, and because many gliomas exhibit deregulated Ras signaling, the authors measured Notch levels and activation in primary samples and cell lines derived from glioblastoma multiforme (GBM) as well as the contribution of Notch pathway activation to astrocytic transformation and growth. Methods. Western blot analysis of Notch 1 expression and activation showed that Notch 1 protein was overexpressed and/or activated in Ras-transformed astrocytes, in three of four GBM cell lines, and in four of five primary GBM samples. Expansion of these studies to assess mRNA expression of components of the Notch signaling pathway by cDNA expression array showed that cDNAs encoding components of the Notch signaling pathway, including the Notch ligand Jagged-1, Notch 3, and the downstream targets of Notch (HES1 and HES2), were also overexpressed relative to nonneoplastic brain controls in 23, 71, and 51% of 35 primary GBMs, respectively. Furthermore, inhibition of Notch signaling by genetic or pharmacological means led to selective suppression of the growth and expression of markers of differentiation in cells exhibiting Notch pathway deregulation. Conclusions. Notch activation contributes to Ras-induced transformation of glial cells and to glioma growth, survival, or both and as such may represent a new target for GBM therapy.

Original languageEnglish (US)
Pages (from-to)417-427
Number of pages11
JournalJournal of neurosurgery
Volume106
Issue number3
DOIs
StatePublished - Mar 1 2007
Externally publishedYes

Keywords

  • Differentiation
  • Glial cell
  • Glioblastoma multiforme
  • Notch 1
  • Notch pathway

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

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  • Cite this

    Kanamori, M., Kawaguchi, T., Nigro, J. M., Feuerstein, B. G., Berger, M. S., Miele, L., & Pieper, R. O. (2007). Contribution of Notch signaling activation to human glioblastoma multiforme. Journal of neurosurgery, 106(3), 417-427. https://doi.org/10.3171/jns.2007.106.3.417