title: Bortezomib sensitizes primary meningioma cells to TRAIL-induced apoptosis by enhancing formation of the death-inducing signaling complex.
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.
authors.affiliation: From the Department of Gastroenterology, Heidelberg University Hospital (RK, TMG); German Cancer Research Center, Division of Signaling and Functional Genomics (CB); Department of Cell and Molecular Biology, Faculty of Medicine Mannheim, Heidelberg University (CB); and HI-STEM gGmbH/German Cancer Research Center Heidelberg (MRS), Heidelberg, Germany; National Cancer Institute Regina Elena (TLH), Rome, Italy; Translational Centre for Regenerative Medicine Leipzig and Faculty of Medicine (HH, L-XX) and Departments of Neurosurgery (L-XX, WK, JM) and Neuropathology (WCM, MB), University of Leipzig, Leipzig, Germany; Ames Laboratory-US DOE, and Department of Physics and Astronomy, Iowa State University, Ames, Iowa (TK); Departments of Cardiology (MK) and Pathology (PS), University Hospital Heidelberg, Heidelberg, Germany; and Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, London, United Kingdom (HW).
authors.forename: Ronald
authors.initials: R
authors.lastname: Koschny
authors.forename: Christina
authors.initials: C
authors.lastname: Boehm
authors.forename: Martin R
authors.initials: MR
authors.lastname: Sprick
authors.forename: Tobias L
authors.initials: TL
authors.lastname: Haas
authors.forename: Heidrun
authors.initials: H
authors.lastname: Holland
authors.forename: Li-Xin
authors.initials: LX
authors.lastname: Xu
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Krupp
authors.forename: Wolf C
authors.initials: WC
authors.lastname: Mueller
authors.forename: Manfred
authors.initials: M
authors.lastname: Bauer
authors.forename: Thomas
authors.initials: T
authors.lastname: Koschny
authors.forename: Marius
authors.initials: M
authors.lastname: Keller
authors.forename: Peter
authors.initials: P
authors.lastname: Sinn
authors.forename: Juergen
authors.initials: J
authors.lastname: Meixensberger
authors.forename: Henning
authors.initials: H
authors.lastname: Walczak
authors.forename: Tom M
authors.initials: TM
authors.lastname: Ganten
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001897:Boronic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib; D057809:HEK293 Cells; D006801:Humans; D008579:Meningioma / Q000188:drug therapy / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000096:biosynthesis*; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000633:toxicity*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; C503369:GRAMD4 protein, human; D024101:Mitochondrial Proteins; D011719:Pyrazines; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D000069286:Bortezomib