Skip to Content
MilliporeSigma
  • Combined inhibition of Bcl-2/Bcl-xL and Usp9X/Bag3 overcomes apoptotic resistance in glioblastoma in vitro and in vivo.

Combined inhibition of Bcl-2/Bcl-xL and Usp9X/Bag3 overcomes apoptotic resistance in glioblastoma in vitro and in vivo.

Oncotarget (2015-05-27)
Georg Karpel-Massler, Chang Shu, Lily Chau, Matei Banu, Marc-Eric Halatsch, Mike-Andrew Westhoff, Yulian Ramirez, Alonzo H Ross, Jeffrey N Bruce, Peter Canoll, Markus D Siegelin
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
MISSION® esiRNA, targeting human BAG3
Sigma-Aldrich
Aphidicolin from Nigrospora sphaerica, ≥98% (HPLC), powder
Sigma-Aldrich
MISSION® esiRNA, targeting mouse Bag3
Sigma-Aldrich
MISSION® esiRNA, targeting mouse Mcl1
Sigma-Aldrich
JC-1, solid
Sigma-Aldrich
MISSION® esiRNA, targeting human MCL1