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, Nhan Tran

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 TNFa-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.

Original languageEnglish (US)
Pages (from-to)12234-12246
Number of pages13
JournalOncotarget
Volume8
Issue number7
DOIs
StatePublished - 2017

Fingerprint

Aurintricarboxylic Acid
Glioblastoma
Glioma
temozolomide
Cell Survival
Tumor Necrosis Factor-alpha
Firefly Luciferases
Preclinical Drug Evaluations
HEK293 Cells
Therapeutics
Brain Neoplasms
Cell Movement
Cell Death
Transcription Factors
Radiation
Apoptosis
Survival
Brain
Proteins

Keywords

  • Aurintricarboxylic acid
  • Fn14
  • Glioblastoma
  • Invasion
  • Survival

ASJC Scopus subject areas

  • Oncology

Cite this

Identification of aurintricarboxylic acid as a selective inhibitor of the TWEAK-Fn14 signaling pathway in glioblastoma cells. / Roos, Alison; Dhruv, Harshil D.; Mathews, Ian T.; Inge, Landon J.; Tuncali, Serdar; Hartman, Lauren K.; Chow, Donald; Millard, Nghia; Yin, Holly H.; Kloss, Jean; Loftus, Joseph C; Winkles, Jeffrey A.; Berens, Michael E.; Tran, Nhan.

In: Oncotarget, Vol. 8, No. 7, 2017, p. 12234-12246.

Research output: Contribution to journalArticle

Roos, A, Dhruv, HD, Mathews, IT, Inge, LJ, Tuncali, S, Hartman, LK, Chow, D, Millard, N, Yin, HH, Kloss, J, Loftus, JC, Winkles, JA, Berens, ME & Tran, N 2017, 'Identification of aurintricarboxylic acid as a selective inhibitor of the TWEAK-Fn14 signaling pathway in glioblastoma cells', Oncotarget, vol. 8, no. 7, pp. 12234-12246. https://doi.org/10.18632/oncotarget.14685
Roos, Alison ; Dhruv, Harshil D. ; Mathews, Ian T. ; Inge, Landon J. ; Tuncali, Serdar ; Hartman, Lauren K. ; Chow, Donald ; Millard, Nghia ; Yin, Holly H. ; Kloss, Jean ; Loftus, Joseph C ; Winkles, Jeffrey A. ; Berens, Michael E. ; Tran, Nhan. / Identification of aurintricarboxylic acid as a selective inhibitor of the TWEAK-Fn14 signaling pathway in glioblastoma cells. In: Oncotarget. 2017 ; Vol. 8, No. 7. pp. 12234-12246.
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AU - Winkles, Jeffrey A.

AU - Berens, Michael E.

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