Research Papers:

Inhibition of deubiquitinases primes glioblastoma cells to apoptosis in vitro and in vivo

Georg Karpel-Massler, Matei A. Banu, Chang Shu, Marc-Eric Halatsch, Mike-Andrew Westhoff, Jeffrey N. Bruce, Peter Canoll and Markus D. Siegelin _

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Oncotarget. 2016; 7:12791-12805. https://doi.org/10.18632/oncotarget.7302

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Georg Karpel-Massler1, Matei A. Banu2, Chang Shu1, Marc-Eric Halatsch3, Mike-Andrew Westhoff4, Jeffrey N. Bruce2, Peter Canoll1, Markus D. Siegelin1

1Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA

2Department of Neurosurgery, Columbia University Medical Center, New York, New York, USA

3Department of Neurosurgery, Ulm University Medical Center, Ulm, Germany

4Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany

Correspondence to:

Markus D. Siegelin, e-mail: [email protected], [email protected]

Keywords: apoptosis, deubiquitinases, Bcl-2 family proteins, glioblastoma

Received: December 08, 2015     Accepted: January 26, 2016     Published: February 10, 2016


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.

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