title: Inhibition of deubiquitinases primes glioblastoma cells to apoptosis in vitro and in vivo.
abstract: It remains a challenge in oncology to identify novel drug regimens to efficiently tackle glioblastoma, the most common primary brain tumor in adults. Here, we target deubiquitinases for glioblastoma therapy by utilizing the small-molecule inhibitor WP1130 which has been characterized as a deubiquitinase inhibitor that interferes with the function of Usp9X. Expression analysis data confirm that Usp9X expression is increased in glioblastoma compared to normal brain tissue indicating its potential as a therapeutic. Consistently, increasing concentrations of WP1130 decrease the cellular viability of established, patient-derived xenograft (PDX) and stem cell-like glioblastoma cells. Specific down-regulation of Usp9X reduces viability in glioblastoma cells mimicking the effects of WP1130. Mechanistically, WP1130 elicits apoptosis and increases activation of caspases. Moreover, WP1130 and siRNAs targeting Usp9X reduce the expression of anti-apoptotic Bcl-2 family members and Inhibitor of Apoptosis Proteins, XIAP and Survivin. Pharmacological and genetic interference with Usp9X efficiently sensitized glioblastoma cells to intrinsic and extrinsic apoptotic stimuli. In addition, single treatment with WP1130 elicited anti-glioma activity in an orthotopic proneural murine model of glioblastoma. Finally, the combination treatment of WP1130 and ABT263 inhibited tumor growth more efficiently than each reagent by its own in vivo without detectable side effects or organ toxicity. Taken together, these results suggest that targeting deubiquitinases for glioma therapy is feasible and effective.
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA.
authors.forename: Georg
authors.initials: G
authors.lastname: Karpel-Massler
authors.affiliation: Department of Neurosurgery, Columbia University Medical Center, New York, New York, USA.
authors.forename: Matei A
authors.initials: MA
authors.lastname: Banu
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA.
authors.forename: Chang
authors.initials: C
authors.lastname: Shu
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 Neurosurgery, Columbia University Medical Center, New York, 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, 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, New York, USA.
authors.forename: Markus D
authors.initials: MD
authors.lastname: Siegelin
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001932:Brain Neoplasms / Q000201:enzymology / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D003487:Cyanoacrylates / Q000494:pharmacology*; D000072017:Deubiquitinating Enzymes / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005909:Glioblastoma / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D051379:Mice; D011725:Pyridines / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D003487:Cyanoacrylates; D004791:Enzyme Inhibitors; D011725:Pyridines; D013449:Sulfonamides; C506234:USP9X protein, human; C519751:degrasyn; D000072017:Deubiquitinating Enzymes; D043222:Ubiquitin Thiolesterase; C528561:navitoclax
keywords: Bcl-2 family proteins; apoptosis; deubiquitinases; glioblastoma