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@ARTICLE{Koschny:127676,
      author       = {R. Koschny and C. Boehm and M. R. Sprick and T. L. Haas and
                      H. Holland and L.-X. Xu and W. Krupp and W. C. Mueller and
                      M. Bauer and T. Koschny and M. Keller and P. Sinn and J.
                      Meixensberger and H. Walczak$^*$ and T. M. Ganten},
      title        = {{B}ortezomib sensitizes primary meningioma cells to
                      {TRAIL}-induced apoptosis by enhancing formation of the
                      death-inducing signaling complex.},
      journal      = {Journal of neuropathology and experimental neurology},
      volume       = {73},
      number       = {11},
      issn         = {1554-6578},
      address      = {Oxford},
      publisher    = {Oxford University Press},
      reportid     = {DKFZ-2017-03699},
      pages        = {1034 - 1046},
      year         = {2014},
      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.},
      keywords     = {Antineoplastic Agents (NLM Chemicals) / Boronic Acids (NLM
                      Chemicals) / GRAMD4 protein, human (NLM Chemicals) /
                      Mitochondrial Proteins (NLM Chemicals) / Pyrazines (NLM
                      Chemicals) / TNF-Related Apoptosis-Inducing Ligand (NLM
                      Chemicals) / TNFSF10 protein, human (NLM Chemicals) /
                      Bortezomib (NLM Chemicals)},
      cin          = {D040},
      ddc          = {610},
      cid          = {I:(DE-He78)D040-20160331},
      pnm          = {314 - Tumor immunology (POF3-314)},
      pid          = {G:(DE-HGF)POF3-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:25289891},
      doi          = {10.1097/NEN.0000000000000129},
      url          = {https://inrepo02.dkfz.de/record/127676},
}