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Oncotarget. 2017 Apr 18;8(16):27300-27313. doi: 10.18632/oncotarget.15934.

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

Author information

1
Division of Pediatric Hematology and Oncology, Department of Child and Adolescent Health, University Medical Center Goettingen, Goettingen, Germany.
2
Institute of Cellular and Molecular Immunology, University Medical Center Goettingen, Goettingen, Germany.
3
Transcriptome and Genome Analysis Laboratory (TAL), Department of Developmental Biochemistry, University Medical Center Goettingen, Goettingen, Germany.
4
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
5
Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.
6
Department of General, Visceral, and Pediatric Surgery, University Medical Center Goettingen, Goettingen, Germany.

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.

KEYWORDS:

CREB binding protein (CBP); ICG-001; Wnt/β-catenin signaling; cell cycle; pediatric high-grade glioma (pedHGG)

PMID:
28460484
PMCID:
PMC5432336
DOI:
10.18632/oncotarget.15934
[Indexed for MEDLINE]
Free PMC Article

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