Identification of aurintricarboxylic acid as a selective inhibitor of the TWEAK-Fn14 signaling pathway in glioblastoma cells
PublisherImpact Journals LLC
MetadataShow full item record
AbstractThe survival of patients diagnosed with glioblastoma (GBM), the most deadly form of brain cancer, is compromised by the proclivity for local invasion into the surrounding normal brain, which prevents complete surgical resection and contributes to therapeutic resistance. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor (TNF) superfamily, can stimulate glioma cell invasion and survival via binding to fibroblast growth factor-inducible 14 (Fn14) and subsequent activation of the transcription factor NF-κB. To discover small molecule inhibitors that disrupt the TWEAK-Fn14 signaling axis, we utilized a cell-based drug-screening assay using HEK293 cells engineered to express both Fn14 and a NF-κB-driven firefly luciferase reporter protein. Focusing on the LOPAC1280 library of 1280 pharmacologically active compounds, we identified aurintricarboxylic acid (ATA) as an agent that suppressed TWEAK-Fn14-NF-κB dependent signaling, but not TNFα-TNFR-NF-κB driven signaling. We demonstrated that ATA repressed TWEAK-induced glioma cell chemotactic migration and invasion via inhibition of Rac1 activation but had no effect on cell viability or Fn14 expression. In addition, ATA treatment enhanced glioma cell sensitivity to both the chemotherapeutic agent temozolomide (TMZ) and radiation-induced cell death. In summary, this work reports a repurposed use of a small molecule inhibitor that targets the TWEAK-Fn14 signaling axis, which could potentially be developed as a new therapeutic agent for treatment of GBM patients.
SponsorsThis work was supported by NIH grant R01 CA130940 and The Ben and Catherine Ivy Foundation.
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85012928601&doi=10.18632%2foncotarget.14685&partnerID=40&md5=d43c3eda0e6bae9387e79a1489941d72; http://hdl.handle.net/10713/10058
- SGEF Is Regulated via TWEAK/Fn14/NF-κB Signaling and Promotes Survival by Modulation of the DNA Repair Response to Temozolomide.
- Authors: Ensign SP, Roos A, Mathews IT, Dhruv HD, Tuncali S, Sarkaria JN, Symons MH, Loftus JC, Berens ME, Tran NL
- Issue date: 2016 Mar
- The Src homology 3 domain-containing guanine nucleotide exchange factor is overexpressed in high-grade gliomas and promotes tumor necrosis factor-like weak inducer of apoptosis-fibroblast growth factor-inducible 14-induced cell migration and invasion via tumor necrosis factor receptor-associated factor 2.
- Authors: Fortin Ensign SP, Mathews IT, Eschbacher JM, Loftus JC, Symons MH, Tran NL
- Issue date: 2013 Jul 26
- Tumor necrosis factor-like weak inducer of apoptosis stimulation of glioma cell survival is dependent on Akt2 function.
- Authors: Fortin SP, Ennis MJ, Savitch BA, Carpentieri D, McDonough WS, Winkles JA, Loftus JC, Kingsley C, Hostetter G, Tran NL
- Issue date: 2009 Nov
- Cdc42 and the guanine nucleotide exchange factors Ect2 and trio mediate Fn14-induced migration and invasion of glioblastoma cells.
- Authors: Fortin SP, Ennis MJ, Schumacher CA, Zylstra-Diegel CR, Williams BO, Ross JT, Winkles JA, Loftus JC, Symons MH, Tran NL
- Issue date: 2012 Jul
- The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-fibroblast growth factor-inducible 14 (Fn14) signaling system regulates glioma cell survival via NFkappaB pathway activation and BCL-XL/BCL-W expression.
- Authors: Tran NL, McDonough WS, Savitch BA, Sawyer TF, Winkles JA, Berens ME
- Issue date: 2005 Feb 4