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 |
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description | 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. |
doi_str_mv | 10.1016/j.yexcr.2024.114091 |
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•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.</description><identifier>ISSN: 0014-4827</identifier><identifier>ISSN: 1090-2422</identifier><identifier>EISSN: 1090-2422</identifier><identifier>DOI: 10.1016/j.yexcr.2024.114091</identifier><identifier>PMID: 38740168</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Brain Neoplasms - genetics ; Brain Neoplasms - metabolism ; Brain Neoplasms - pathology ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Epithelial-Mesenchymal Transition - genetics ; Gene Expression Regulation, Neoplastic ; Glioblastoma - genetics ; Glioblastoma - metabolism ; Glioblastoma - pathology ; Glioma cells ; Humans ; Invasion and migration abilities ; Mice ; Mice, Nude ; Neoplasm Invasiveness ; Proneural–mesenchymal transition ; Signal Transduction ; Sulfonamides - pharmacology ; Toll-like receptor 4 ; Toll-Like Receptor 4 - genetics ; Toll-Like Receptor 4 - metabolism ; Xenograft Model Antitumor Assays</subject><ispartof>Experimental cell research, 2024-06, Vol.439 (1), p.114091, Article 114091</ispartof><rights>2024 Elsevier Inc.</rights><rights>Copyright © 2024 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c309t-1fbc0c1b13d4b05bcb261bf87c77cb4af561ca182ca9770f4a6f0f3810351bef3</cites><orcidid>0009-0004-4681-7005</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.yexcr.2024.114091$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38740168$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Feng, Zibin</creatorcontrib><creatorcontrib>Chen, Guangliang</creatorcontrib><creatorcontrib>Huang, Yunfan</creatorcontrib><creatorcontrib>Zhang, Kai</creatorcontrib><creatorcontrib>Wu, Guanzhang</creatorcontrib><creatorcontrib>Xing, Weixin</creatorcontrib><creatorcontrib>Wu, Yue</creatorcontrib><creatorcontrib>Zhou, Youxin</creatorcontrib><creatorcontrib>Sun, Chunming</creatorcontrib><title>TAK-242 inhibits glioblastoma invasion, migration, and proneural–mesenchymal transition by inhibiting TLR4 signaling</title><title>Experimental cell research</title><addtitle>Exp Cell Res</addtitle><description>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.</description><subject>Animals</subject><subject>Brain Neoplasms - genetics</subject><subject>Brain Neoplasms - metabolism</subject><subject>Brain Neoplasms - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement</subject><subject>Cell Proliferation</subject><subject>Epithelial-Mesenchymal Transition - genetics</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Glioblastoma - genetics</subject><subject>Glioblastoma - metabolism</subject><subject>Glioblastoma - pathology</subject><subject>Glioma cells</subject><subject>Humans</subject><subject>Invasion and migration abilities</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Neoplasm Invasiveness</subject><subject>Proneural–mesenchymal transition</subject><subject>Signal Transduction</subject><subject>Sulfonamides - pharmacology</subject><subject>Toll-like receptor 4</subject><subject>Toll-Like Receptor 4 - genetics</subject><subject>Toll-Like Receptor 4 - metabolism</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0014-4827</issn><issn>1090-2422</issn><issn>1090-2422</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1OwzAQRi0EglI4ARLKkgUpM4mbuAsWqOJPVEJCZW3Zjt26Shyw04ruuAM35CS4FFiy8th6843nEXKCMEDA4mIxWOs35QcZZHSASGGEO6SHMII0o1m2S3oASFPKsvKAHIawAADGsNgnBzkraYxgPbKaXj1s8MS6uZW2C8mstq2sRejaRsTXlQi2dedJY2dedN-lcFXy4lunl17Un-8fjQ7aqfm6EXXSeeGC3XCJXP-GWjdLppMnmgQ7c6KO1yOyZ0Qd9PHP2SfPN9fT8V06eby9H19NUpXDqEvRSAUKJeYVlTCUSmYFSsNKVZZKUmGGBSqBLFNiVJZgqCgMmJwh5EOU2uR9crbNjf99XerQ8cYGpetaON0uA89hSBmFsmARzbeo8m0IXhv-4m0j_Joj8I1wvuDfwvlGON8Kj12nPwOWstHVX8-v4QhcbgEd11xZ7XlQNurSlfVadbxq7b8DvgAbO5VT</recordid><startdate>20240601</startdate><enddate>20240601</enddate><creator>Feng, Zibin</creator><creator>Chen, Guangliang</creator><creator>Huang, Yunfan</creator><creator>Zhang, Kai</creator><creator>Wu, Guanzhang</creator><creator>Xing, Weixin</creator><creator>Wu, Yue</creator><creator>Zhou, Youxin</creator><creator>Sun, Chunming</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0009-0004-4681-7005</orcidid></search><sort><creationdate>20240601</creationdate><title>TAK-242 inhibits glioblastoma invasion, migration, and proneural–mesenchymal transition by inhibiting TLR4 signaling</title><author>Feng, Zibin ; Chen, Guangliang ; Huang, Yunfan ; Zhang, Kai ; Wu, Guanzhang ; Xing, Weixin ; Wu, Yue ; Zhou, Youxin ; Sun, Chunming</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c309t-1fbc0c1b13d4b05bcb261bf87c77cb4af561ca182ca9770f4a6f0f3810351bef3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animals</topic><topic>Brain Neoplasms - genetics</topic><topic>Brain Neoplasms - metabolism</topic><topic>Brain Neoplasms - pathology</topic><topic>Cell Line, Tumor</topic><topic>Cell Movement</topic><topic>Cell Proliferation</topic><topic>Epithelial-Mesenchymal Transition - genetics</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Glioblastoma - genetics</topic><topic>Glioblastoma - metabolism</topic><topic>Glioblastoma - pathology</topic><topic>Glioma cells</topic><topic>Humans</topic><topic>Invasion and migration abilities</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Neoplasm Invasiveness</topic><topic>Proneural–mesenchymal transition</topic><topic>Signal Transduction</topic><topic>Sulfonamides - pharmacology</topic><topic>Toll-like receptor 4</topic><topic>Toll-Like Receptor 4 - genetics</topic><topic>Toll-Like Receptor 4 - metabolism</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Feng, Zibin</creatorcontrib><creatorcontrib>Chen, Guangliang</creatorcontrib><creatorcontrib>Huang, Yunfan</creatorcontrib><creatorcontrib>Zhang, Kai</creatorcontrib><creatorcontrib>Wu, Guanzhang</creatorcontrib><creatorcontrib>Xing, Weixin</creatorcontrib><creatorcontrib>Wu, Yue</creatorcontrib><creatorcontrib>Zhou, Youxin</creatorcontrib><creatorcontrib>Sun, Chunming</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Experimental cell research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Feng, Zibin</au><au>Chen, Guangliang</au><au>Huang, Yunfan</au><au>Zhang, Kai</au><au>Wu, Guanzhang</au><au>Xing, Weixin</au><au>Wu, Yue</au><au>Zhou, Youxin</au><au>Sun, Chunming</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TAK-242 inhibits glioblastoma invasion, migration, and proneural–mesenchymal transition by inhibiting TLR4 signaling</atitle><jtitle>Experimental cell research</jtitle><addtitle>Exp Cell Res</addtitle><date>2024-06-01</date><risdate>2024</risdate><volume>439</volume><issue>1</issue><spage>114091</spage><pages>114091-</pages><artnum>114091</artnum><issn>0014-4827</issn><issn>1090-2422</issn><eissn>1090-2422</eissn><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.
•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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>38740168</pmid><doi>10.1016/j.yexcr.2024.114091</doi><orcidid>https://orcid.org/0009-0004-4681-7005</orcidid></addata></record> |
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subjects | Animals Brain Neoplasms - genetics Brain Neoplasms - metabolism Brain Neoplasms - pathology Cell Line, Tumor Cell Movement Cell Proliferation Epithelial-Mesenchymal Transition - genetics Gene Expression Regulation, Neoplastic Glioblastoma - genetics Glioblastoma - metabolism Glioblastoma - pathology Glioma cells Humans Invasion and migration abilities Mice Mice, Nude Neoplasm Invasiveness Proneural–mesenchymal transition Signal Transduction Sulfonamides - pharmacology Toll-like receptor 4 Toll-Like Receptor 4 - genetics Toll-Like Receptor 4 - metabolism Xenograft Model Antitumor Assays |
title | TAK-242 inhibits glioblastoma invasion, migration, and proneural–mesenchymal transition by inhibiting TLR4 signaling |
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