title: Propentofylline inhibits glioblastoma cell invasion and survival by targeting the TROY signaling pathway.
abstract: Glioblastoma (GBM) is the most common primary tumor of the CNS and carries a dismal prognosis. The aggressive invasion of GBM cells into the surrounding normal brain makes complete resection impossible, significantly increases resistance to the standard therapy regimen, and virtually assures tumor recurrence. Median survival for newly diagnosed GBM is 14.6 months and declines to 8 months for patients with recurrent GBM. New therapeutic strategies that target the molecular drivers of invasion are required for improved clinical outcome. We have demonstrated that TROY (TNFRSF19), a member of the TNFR super-family, plays an important role in GBM invasion and resistance. Knockdown of TROY expression inhibits GBM cell invasion, increases sensitivity to temozolomide, and prolongs survival in an intracranial xenograft model. Propentofylline (PPF), an atypical synthetic methylxanthine compound, has been extensively studied in Phase II and Phase III clinical trials for Alzheimer's disease and vascular dementia where it has demonstrated blood-brain permeability and minimal adverse side effects. Here we showed that PPF decreased GBM cell expression of TROY, inhibited glioma cell invasion, and sensitized GBM cells to TMZ. Mechanistically, PPF decreased glioma cell invasion by modulating TROY expression and downstream signaling, including AKT, NF-κB, and Rac1 activation. Thus, PPF may provide a pharmacologic approach to target TROY, inhibit cell invasion, and reduce therapeutic resistance in GBM.
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute, 445 N 5th St., Phoenix, AZ, 85004, USA.
authors.forename: Harshil D
authors.initials: HD
authors.lastname: Dhruv
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute, 445 N 5th St., Phoenix, AZ, 85004, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Roos
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute, 445 N 5th St., Phoenix, AZ, 85004, USA.|Medical Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, AZ, 85006, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Tomboc
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute, 445 N 5th St., Phoenix, AZ, 85004, USA.
authors.forename: Serdar
authors.initials: S
authors.lastname: Tuncali
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute, 445 N 5th St., Phoenix, AZ, 85004, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Chavez
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute, 445 N 5th St., Phoenix, AZ, 85004, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Mathews
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute, 445 N 5th St., Phoenix, AZ, 85004, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Berens
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic Arizona, Scottsdale, AZ, 85259, USA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Loftus
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute, 445 N 5th St., Phoenix, AZ, 85004, USA. ntran@tgen.org.
authors.forename: Nhan L
authors.initials: NL
authors.lastname: Tran
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D018696:Neuroprotective Agents / Q000494:pharmacology; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014970:Xanthines / Q000494:pharmacology*
chemical_list: D016328:NF-kappa B; D018696:Neuroprotective Agents; D018124:Receptors, Tumor Necrosis Factor; C411850:TNFRSF19 protein, human; D014970:Xanthines; C032114:propentofylline
keywords: Glioblastoma; Invasion; Resistance; Survival; TROY