Combined inhibition of Bcl-2/Bcl-xL and Usp9X/Bag3 overcomes apoptotic resistance in glioblastoma in vitro and in vivo
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Georg Karpel-Massler1, Chang Shu1, Lily Chau1, Matei Banu2, Marc-Eric Halatsch3, Mike-Andrew Westhoff4, Yulian Ramirez5, Alonzo H. Ross5, Jeffrey N. Bruce2, Peter Canoll1 and Markus D. Siegelin1
1 Department of Pathology and Cell Biology, Columbia University Medical Center, New York, USA
2 Department of Neurosurgery, Columbia University Medical Center, New York, USA
3 Department of Neurosurgery, Ulm University Medical Center, Ulm, Germany
4 Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany
5 Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Massachusetts, USA
Markus D. Siegelin, email:
Keywords: glioblastoma, BH3-mimetic, apoptotic resistance, ABT263, GX15-070
Received: March 12, 2015 Accepted: April 10, 2015 Published: May 04, 2015
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.
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