TAK-242 inhibits glioblastoma invasion, migration, and proneural–mesenchymal transition by inhibiting TLR4 signaling

Resatorvid (TAK-242), a small-molecule inhibitor of Toll-like receptor 4 (TLR4), has the ability to cross the blood-brain barrier (BBB). In this study, we explored the role of TAK-242 on glioblastoma (GBM) invasion, migration, and proneural–mesenchymal transition (PMT). RNA sequencing (RNA-Seq) data...

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Veröffentlicht in:Experimental cell research 2024-06, Vol.439 (1), p.114091, Article 114091
Hauptverfasser: Feng, Zibin, Chen, Guangliang, Huang, Yunfan, Zhang, Kai, Wu, Guanzhang, Xing, Weixin, Wu, Yue, Zhou, Youxin, Sun, Chunming
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Sprache:eng
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Zusammenfassung:Resatorvid (TAK-242), a small-molecule inhibitor of Toll-like receptor 4 (TLR4), has the ability to cross the blood-brain barrier (BBB). In this study, we explored the role of TAK-242 on glioblastoma (GBM) invasion, migration, and proneural–mesenchymal transition (PMT). RNA sequencing (RNA-Seq) data and full clinical information of glioma patients were downloaded from the Chinese Glioma Genome Atlas (CGGA) and the Cancer Genome Atlas (TCGA) cohorts and then analyzed using R language; patients were grouped based on proneural (PN) and mesenchymal (MES) subtypes. Bioinformatics analysis was used to detect the difference in survival and TLR4-pathway expression between these groups. Cell viability assay, wound-healing test, and transwell assay, as well as an intracranial xenotransplantation mice model, were used to assess the functional role of TAK-242 in GBM in vitro and in vivo. RNA-Seq, Western blot, and immunofluorescence were employed to investigate the possible mechanism. TLR4 expression in GBM was significantly higher than in normal brain tissue and upregulated the expression of MES marker genes. Moreover, TAK-242 inhibited GBM progression in vitro and in vivo via linking with PMT, which could be a novel treatment strategy for inhibiting GBM recurrence. •TAK-242 selectively inhibits glioblastoma (GBM) by targeting overexpressed Toll-like receptor 4 (TLR4).•TAK-242 robustly suppresses proneural–mesenchymal transition (PMT), impeding GBM progression.•Elevated TLR4 levels in GBM identify TAK-242 as a promising therapeutic target.•TAK-242 introduces a targeted approach with therapeutic potential for inhibiting GBM recurrence.
ISSN:0014-4827
1090-2422
1090-2422
DOI:10.1016/j.yexcr.2024.114091