Proteasome Inhibition Enhances The Effect of Bikdd Gene Therapy

<p>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 <em>in vitro</em> and <em>in vivo</em> 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.</p>

Name thesis:degree_name

Masters of Science (MS)

Level thesis:degree_level

Thesis (MS)

Year dc:date.available

2014

Author dc:creator

• Sun, Ye

Contributors dc:contributor

• Mien-Chie Hung
• Paul Chiao
• Hui-Kuan Lin

• BikDD
• Gene Therapy
• Proteasome Inhibition
• Combination Therapy
• Apoptosis
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/464

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1505