期刊
ONCOTARGET
卷 8, 期 16, 页码 27300-27313出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.15934
关键词
ICG-001; pediatric high-grade glioma (pedHGG); Wnt/beta-catenin signaling; CREB binding protein (CBP); cell cycle
资金
- German society of Menschen fur Kinder e.V.
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 beta-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 beta-catenin/Wnt-signaling pathway-inhibition by the beta-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 beta-catenin/Wnt-signaling. RNA-sequencing analyses support a Wnt/beta-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/beta-catenin signaling-activity.
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