The β-catenin/CBP-antagonist ICG-001 inhibits pediatric glioma tumorigenicity in a Wnt-independent manner

Maria Wiese, Neele Walther, Christopher Diederichs, Fabian Schill, Sebastian Monecke, Gabriela Salinas, Dominik Sturm, Stefan M. Pfister, Ralf Dressel, Steven A. Johnsen, Christof M. Kramm

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Pediatric high-grade gliomas (pedHGG) belong to the most aggressive cancers in children with a poor prognosis due to a lack of efficient therapeutic strategies. The β-catenin/Wnt-signaling pathway was shown to hold promising potential as a treatment target in adult high-grade gliomas by abrogating tumor cell invasion and the acquisition of stem cell-like characteristics. Since pedHGG differ from their adult counterparts in genetically and biologically we aimed to investigate the effects of β-catenin/Wnt-signaling pathway-inhibition by the β-catenin/CBP antagonist ICG-001 in pedHGG cell lines. In contrast to adult HGG, pedHGG cells displayed minimal detectable canonical Wnt-signaling activity. Nevertheless, low doses of ICG-001 inhibited cell migration/invasion, tumorsphere- and colony formation, proliferation in vitro as well as tumor growth in vivo/ovo, suggesting that ICG-001 affects pedHGG tumor cell characteristics independent of β-catenin/Wnt-signaling. RNA-sequencing analyses support a Wnt/β-catenin-independent effect of ICG-001 on target gene transcription, revealing strong effects on genes involved in cellular metabolic/biosynthetic processes and cell cycle progression. Among these, high mRNA expression of cell cycle regulator JDP2 was found to confer a better prognosis for pedHGG patients. In conclusion, ICG-001 might offer an effective treatment option for pedHGG patients functioning to regulate cell phenotype and gene expression programs in absence of Wnt/β-catenin signaling-activity.

Original languageEnglish (US)
Pages (from-to)27300-27313
Number of pages14
JournalOncotarget
Volume8
Issue number16
DOIs
StatePublished - Jan 1 2017

Keywords

  • CREB binding protein (CBP)
  • Cell cycle
  • ICG-001
  • Pediatric high-grade glioma (pedHGG)
  • Wnt/β-catenin signaling

ASJC Scopus subject areas

  • Oncology

Fingerprint Dive into the research topics of 'The β-catenin/CBP-antagonist ICG-001 inhibits pediatric glioma tumorigenicity in a Wnt-independent manner'. Together they form a unique fingerprint.

  • Cite this

    Wiese, M., Walther, N., Diederichs, C., Schill, F., Monecke, S., Salinas, G., Sturm, D., Pfister, S. M., Dressel, R., Johnsen, S. A., & Kramm, C. M. (2017). The β-catenin/CBP-antagonist ICG-001 inhibits pediatric glioma tumorigenicity in a Wnt-independent manner. Oncotarget, 8(16), 27300-27313. https://doi.org/10.18632/oncotarget.15934