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

Zibin Feng; Guangliang Chen; Yunfan Huang; Kai Zhang; Guanzhang Wu; Weixin Xing; Yue Wu; Youxin Zhou; Chunming Sun

doi:10.1016/j.yexcr.2024.114091

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

Exp Cell Res. 2024 May 11;439(1):114091. doi: 10.1016/j.yexcr.2024.114091. Online ahead of print.

Authors

Zibin Feng¹, Guangliang Chen², Yunfan Huang², Kai Zhang², Guanzhang Wu², Weixin Xing², Yue Wu², Youxin Zhou³, Chunming Sun⁴

Affiliations

¹ Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Jiangsu, Suzhou 215006, China; Department of Neurosurgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an 710054, Shaanxi Province, China.
² Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Jiangsu, Suzhou 215006, China.
³ Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Jiangsu, Suzhou 215006, China. Electronic address: brain_lab@suda.edu.cn.
⁴ Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Jiangsu, Suzhou 215006, China. Electronic address: sunchunming_suda@163.com.

PMID: 38740168
DOI: 10.1016/j.yexcr.2024.114091

Abstract

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.

Keywords: Glioma cells; Invasion and migration abilities; Proneural–mesenchymal transition; Toll-like receptor 4.