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.
Highlights
Glioblastoma (GBM), or grade IV astrocytoma, is the most common primary malignant intracranial tumor in adults [1]
We demonstrated that aurintricarboxylic acid (ATA) repressed Tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-induced glioma cell chemotactic migration and invasion via inhibition of Rac1 activation but had no effect on cell viability or factor-inducible 14 (Fn14) expression
Since ATA suppressed TWEAK stimulation of NF-κB activity in HEK293 cells, we investigated the effects of ATA on signaling cascades downstream of Fn14 using two established glioma cell lines (T98G and A172) and the GBM patient-derived xenograft (PDX) line GBM44
Summary
Glioblastoma (GBM), or grade IV astrocytoma, is the most common primary malignant intracranial tumor in adults [1]. Often following along myelinated white matter www.impactjournals.com/oncotarget tracts, the neoplastic cells disperse from the tumor border and infiltrate the normal brain parenchyma [9,10,11]. This invasive sub-population is inherently resistant to cytotoxic therapy, which precludes effective clinical management of GBM and results in tumor recurrence [5, 12, 13]. ATA suppressed TWEAK-induced glioma survival in the presence of genotoxic stress Taken together, these data demonstrate that ATA may be a potential therapeutic agent to limit invasion and enhance chemotherapeutic drug efficacy in GBM
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