Proteasome inhibition enhances the killing effect of BikDD gene therapy

Ye, S., Ponz-Sarvise, M., Chang, S. S., Chang, W. C., Chen, C. H., Hsu, J. L., Hung, M. C. (April 2015) Proteasome inhibition enhances the killing effect of BikDD gene therapy. American Journal of Translational Research, 7 (2). pp. 319-327. ISSN 19438141



BikDD, a phosphorylation-mimic mutant of pro-apoptotic protein Bik, elicits strong apoptosis in cancer cells when introduced via an expression platform termed VP16-GAL4-WPRE integrated systemic amplifier (VISA) under the control of a cancer-specific promoter both in vitro and in vivo. C-VISA-BikDD expression plasmid encapsulated in liposomes is currently in the process to initiate a phase I clinical trial for pancreatic cancer. In this study, we report a potential combination approach of BikDD with proteasome inhibitors on the basis of our findings that exogenously expressed BikDD protein undergoes proteasome-mediated degradation via both ubiquitin-dependent and -independent pathways. Inhibition of proteasome increases the protein stability of BikDD, enhancing the apoptotic effect of BikDD. Hence, high proteasome activity may be a mechanism by which intrinsic and acquired resistance occurs in BikDD gene therapy, and a combination therapy with current clinically approved proteasome inhibitor may overcome resistance. © 2015, E-Century Publishing Corporation. All right reserved.

Item Type: Paper
Uncontrolled Keywords: Apoptosis BikDD Combinational therapy Proteasome inhibition
Subjects: diseases & disorders > cancer
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > apoptosis
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > Protease
CSHL Authors:
Communities: CSHL labs > Tuveson lab
Depositing User: Matt Covey
Date: April 2015
Date Deposited: 17 Apr 2015 15:18
Last Modified: 24 Apr 2015 19:27
PMCID: PMC4399095
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