Department of Biochemistry and Molecular Pharmacology
Cancer Biology | Neoplasms | Oncology
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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Citation: Oncotarget. 2015 Jun 10;6(16):14507-21. Link to article on publisher's site
DOI of Published Version
ABT263, BH3-mimetic, GX15-070, apoptotic resistance, glioblastoma
Karpel-Massler, Georg; Shu, Chang; Chau, Lily; Banu, Matei; Halatsch, Marc-Eric; Westhoff, Mike-Andrew; Ramirez, Yulian P.; Ross, Alonzo H.; Bruce, Jeffrey N.; Canoll, Peter; and Siegelin, Markus D., "Combined inhibition of Bcl-2/Bcl-xL and Usp9X/Bag3 overcomes apoptotic resistance in glioblastoma in vitro and in vivo" (2015). Open Access Articles. 2711.
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