Date of Graduation
Masters of Science (MS)
BikDD is a phosphorylation mimic mutant form of pro-apoptotic protein Bik, and possesses a stronger apoptosis induction capability. By constructing into a highly amplified “VISA” (VP16-GAL4-WPRE integrated systemic amplifier) system under the control of a cancer specific promoter, previous studies have verified the specific killing effect of BikDD in cancer cells both in in vitro and in vivo models. C-VISA-BikDD delivered by liposome has been approved by FDA for clinical trial in advanced pancreatic cancer. In this study, we proposed proteasome inhibition as a combinational therapy strategy with BikDD gene therapy to enhance the clinical benefits. Proteasome inhibition stabilized exogenously expressed BikDD protein, and significantly enhanced the apoptosis induction effect of BikDD. Studies on detailed mechanism for BikDD degradation revealed that both ubiquitylation dependent and ubiquitylation independent pathways contribute to BikDD degradation. High proteasome activity might be a potential mechanism for both intrinsic and acquired resistance in BikDD gene therapy, and combinational therapy with current clinically approved proteasome inhibitor would be helpful for overcoming the resistance.
BikDD, Gene Therapy, Proteasome Inhibition, Combination Therapy, Apoptosis