Bortezomib sensitizes primary meningioma cells to TRAIL-induced apoptosis by enhancing formation of the death-inducing signaling complex

Tobias Longin Haas, Ronald Koschny, Christina Boehm, Martin R. Sprick, Heidrun Holland, Li-Xin Xu, Wolf C. Mueller, Manfred Bauer, Thomas Koschny, Marius Keller, Peter Sinn, Juergen Meixensberger, Henning Walczak, Tom M. Ganten

Risultato della ricerca: Contributo in rivistaArticolo in rivista

14 Citazioni (Scopus)

Abstract

A meningioma is the most common primary intracranial tumor in adults. Here, we investigated the therapeutic potential of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in 37 meningiomas. Freshly isolated primary meningioma cells were treated with TRAIL with or without different sensitizing protocols, and apoptotic cell death was then quantified. Mechanisms of TRAIL sensitization were determined by a combination of Western blotting, flow cytometry, receptor complex immunoprecipitation, and siRNA-mediated knockdown experiments. Tumor necrosis factor-related apoptosis-inducing ligand receptor expression was analyzed using immunohistochemistry and quantified by an automated software-based algorithm. Primary tumor cells from 11 (29.7%) tumor samples were sensitive to TRAIL-induced apoptosis, 12 (32.4%) were intermediate TRAIL resistant, and 14 (37.8%) were completely TRAIL resistant. We tested synergistic apoptosis-inducing cotreatment strategies and determined that only the proteasome inhibitor bortezomib potently enhanced expression of the TRAIL receptors TRAIL-R1 and/or TRAIL-R2, the formation of the TRAIL death-inducing signaling complex, and activation of caspases; this treatment resulted in sensitization of all TRAIL-resistant meningioma samples to TRAIL-induced apoptosis. Bortezomib pretreatment induced NOXA expression and downregulated c-FLIP, neither of which caused the TRAIL-sensitizing effect. Native TRAIL receptor expression could not predict primary TRAIL sensitivity. This first report on TRAIL sensitivity of primary meningioma cells demonstrates that TRAIL/bortezomib cotreatment may represent a novel therapeutic option for meningiomas.
Lingua originaleEnglish
pagine (da-a)1034-1046
Numero di pagine13
RivistaJournal of Neuropathology and Experimental Neurology
Volume73
DOI
Stato di pubblicazionePubblicato - 2014

Keywords

  • Antineoplastic Agents
  • Apoptosis
  • Boronic Acids
  • Bortezomib
  • HEK293 Cells
  • Humans
  • Meningioma
  • Mitochondrial Proteins
  • Pyrazines
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Cells, Cultured

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