title: Combined inhibition of Bcl-2/Bcl-xL and Usp9X/Bag3 overcomes apoptotic resistance in glioblastoma in vitro and in vivo.
abstract: Despite great efforts taken to advance therapeutic measures for patients with glioblastoma, the clinical prognosis remains grim. The antiapoptotic Bcl-2 family protein Mcl-1 is overexpressed in glioblastoma and represents an important resistance factor to the BH-3 mimetic ABT263. In this study, we show that combined treatment with ABT263 and GX15-070 overcomes apoptotic resistance in established glioblastoma cell lines, glioma stem-like cells and primary cultures. Moreover, this treatment regimen also proves to be advantageous in vivo. On the molecular level, GX15-070 enhanced apoptosis by posttranslational down-regulation of the deubiquitinase, Usp9X, and the chaperone Bag3, leading to a sustained depletion of Mcl-1 protein levels. Moreover, knock-down of Usp9X or Bag3 depleted endogenous Mcl-1 protein levels and in turn enhanced apoptosis induced through Bcl-2/Bcl-xL inhibition. In conclusion, combined treatment with ABT263 and GX15-070 results in a significantly enhanced anti-cancer activity in vitro as well as in vivo in the setting of glioblastoma. Both drugs, ABT263 and GX15-070 have been evaluated in clinical studies which facilitates the translational aspect of taking this combinatorial approach to the clinical setting. Furthermore we present a novel mechanism by which GX15-070 counteracts Mcl-1 expression which may lay a foundation for a novel target in cancer therapy.
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, USA.
authors.forename: Georg
authors.initials: G
authors.lastname: Karpel-Massler
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, USA.
authors.forename: Chang
authors.initials: C
authors.lastname: Shu
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, USA.
authors.forename: Lily
authors.initials: L
authors.lastname: Chau
authors.affiliation: Department of Neurosurgery, Columbia University Medical Center, New York, USA.
authors.forename: Matei
authors.initials: M
authors.lastname: Banu
authors.affiliation: Department of Neurosurgery, Ulm University Medical Center, Ulm, Germany.
authors.forename: Marc-Eric
authors.initials: ME
authors.lastname: Halatsch
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
authors.forename: Mike-Andrew
authors.initials: MA
authors.lastname: Westhoff
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Massachusetts, USA.
authors.forename: Yulian
authors.initials: Y
authors.lastname: Ramirez
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Massachusetts, USA.
authors.forename: Alonzo H
authors.initials: AH
authors.lastname: Ross
authors.affiliation: Department of Neurosurgery, Columbia University Medical Center, New York, USA.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Bruce
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Canoll
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, USA.
authors.forename: Markus D
authors.initials: MD
authors.lastname: Siegelin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001932:Brain Neoplasms / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D005909:Glioblastoma / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D016513:Mice, SCID; D015394:Molecular Structure; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014162:Transfection; D043222:Ubiquitin Thiolesterase; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C498806:Bag3 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D010450:Endopeptidases; D043222:Ubiquitin Thiolesterase; C404328:Usp9x protein, mouse
keywords: ABT263; BH3-mimetic; GX15-070; apoptotic resistance; glioblastoma