title: Identification of aurintricarboxylic acid as a selective inhibitor of the TWEAK-Fn14 signaling pathway in glioblastoma cells.
abstract: The 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.
authors.affiliation: Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, Arizona 85259, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Roos
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: Harshil D
authors.initials: HD
authors.lastname: Dhruv
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: Ian T
authors.initials: IT
authors.lastname: Mathews
authors.affiliation: Norton Thoracic Institute, St Joseph's Hospital and Medical Center, Phoenix, AZ 85004, USA.
authors.forename: Landon J
authors.initials: LJ
authors.lastname: Inge
authors.affiliation: Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, Arizona 85259, USA.
authors.forename: Serdar
authors.initials: S
authors.lastname: Tuncali
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: Lauren K
authors.initials: LK
authors.lastname: Hartman
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Chow
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: Nghia
authors.initials: N
authors.lastname: Millard
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: Holly H
authors.initials: HH
authors.lastname: Yin
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic Arizona, Scottsdale, Arizona 85259, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Kloss
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic Arizona, Scottsdale, Arizona 85259, USA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Loftus
authors.affiliation: Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Winkles
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Berens
authors.affiliation: Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, Arizona 85259, USA.
authors.forename: Nhan L
authors.initials: NL
authors.lastname: Tran
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D001312:Aurintricarboxylic Acid / Q000737:chemistry / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D000074049:Cytokine TWEAK; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D008819:Mice, Nude; D015394:Molecular Structure; D034622:RNA Interference; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D000074050:TWEAK Receptor; D000077204:Temozolomide; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D018906:Antineoplastic Agents, Alkylating; D000074049:Cytokine TWEAK; D018124:Receptors, Tumor Necrosis Factor; D054852:Small Molecule Libraries; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; D048069:Tumor Necrosis Factors; D001312:Aurintricarboxylic Acid; D003606:Dacarbazine; D000077204:Temozolomide
keywords: Fn14; aurintricarboxylic acid; glioblastoma; invasion; survival