title: Proteasome inhibition enhances the killing effect of BikDD gene therapy.
abstract: 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.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas 77030, USA ; Graduate School of Biomedical Sciences, The University of Texas Houston Health Science Center Houston, Texas 77030, USA ; Present Address: Department of Biological Sciences, Florida Atlantic University Boca Raton, FL 33431, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas 77030, USA ; Present Address: Cold Spring Harbor Laboratory Cold Spring Harbor, NY 11724, USA.
authors.forename: Mariano
authors.initials: M
authors.lastname: Ponz-Sarvise
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas 77030, USA ; Graduate School of Biomedical Sciences, The University of Texas Houston Health Science Center Houston, Texas 77030, USA.
authors.forename: Shih-Shin
authors.initials: SS
authors.lastname: Chang
authors.affiliation: Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University Taichung 404, Taiwan.
authors.forename: Wei-Chao
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Genomics Research Center, Academia Sinica Nankang, Taipei 105, Taiwan.
authors.forename: Chung-Hsuan
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas 77030, USA ; Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University Taichung 404, Taiwan ; Department of Biotechnology, Asia University Taichung 404, Taiwan.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hsu
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas 77030, USA ; Graduate School of Biomedical Sciences, The University of Texas Houston Health Science Center Houston, Texas 77030, USA ; Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University Taichung 404, Taiwan ; Department of Biotechnology, Asia University Taichung 404, Taiwan.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
keywords: BikDD; apoptosis; combinational therapy; proteasome inhibition