The β-catenin/CBP-antagonist ICG-001 inhibits pediatric glioma tumorigenicity in a Wnt-independent manner
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Maria Wiese1, Neele Walther1, Christopher Diederichs1, Fabian Schill1, Sebastian Monecke2, Gabriela Salinas3, Dominik Sturm4, Stefan M. Pfister4,5, Ralf Dressel2, Steven A. Johnsen6, Christof M. Kramm1
1Division of Pediatric Hematology and Oncology, Department of Child and Adolescent Health, University Medical Center Goettingen, Goettingen, Germany
2Institute of Cellular and Molecular Immunology, University Medical Center Goettingen, Goettingen, Germany
3Transcriptome and Genome Analysis Laboratory (TAL), Department of Developmental Biochemistry, University Medical Center Goettingen, Goettingen, Germany
4Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
5Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
6Department of General, Visceral, and Pediatric Surgery, University Medical Center Goettingen, Goettingen, Germany
Maria Wiese, email: firstname.lastname@example.org
Keywords: ICG-001, pediatric high-grade glioma (pedHGG), Wnt/β-catenin signaling, CREB binding protein (CBP), cell cycle
Received: July 14, 2016 Accepted: February 20, 2017 Published: March 06, 2017
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.
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