Oncotarget

Research Papers:

Identification of aurintricarboxylic acid as a selective inhibitor of the TWEAK-Fn14 signaling pathway in glioblastoma cells

Alison Roos _, Harshil D. Dhruv, Ian T. Mathews, Landon J. Inge, Serdar Tuncali, Lauren K. Hartman, Donald Chow, Nghia Millard, Holly H. Yin, Jean Kloss, Joseph C. Loftus, Jeffrey A. Winkles, Michael E. Berens and Nhan L. Tran

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Oncotarget. 2017; 8:12234-12246. https://doi.org/10.18632/oncotarget.14685

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Abstract

Alison Roos1,*, Harshil D. Dhruv2,*, Ian T. Mathews2, Landon J. Inge3, Serdar Tuncali1, Lauren K. Hartman2, Donald Chow2, Nghia Millard2, Holly H. Yin2, Jean Kloss4, Joseph C. Loftus4, Jeffrey A. Winkles5, Michael E. Berens2, Nhan L. Tran1

1Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, Arizona 85259, USA

2Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, Arizona 85004, USA

3Norton Thoracic Institute, St Joseph’s Hospital and Medical Center, Phoenix, AZ 85004, USA

4Department of Biochemistry and Molecular Biology, Mayo Clinic Arizona, Scottsdale, Arizona 85259, USA

5Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA

*These authors have contributed equally to this work

Correspondence to:

Nhan L. Tran, email: [email protected]

Keywords: glioblastoma, survival, invasion, Fn14, aurintricarboxylic acid

Received: August 15, 2016    Accepted: December 26, 2016    Published: January 17, 2017

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.


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