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.
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.
Am J Transl Res. 2015 Feb 15;7(2):319-27. eCollection 2015.
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.
BikDD 是一种促凋亡蛋白 Bik 的磷酸化模拟突变体，当通过一种名为 VP16-GAL4-WPRE 整合系统放大器 (VISA) 的表达平台导入时，在体外和体内均受特定于癌症的启动子控制，可引发强烈的癌细胞凋亡。封装在脂质体中的 C-VISA-BikDD 表达质粒目前正在启动用于胰腺癌的 I 期临床试验。在这项研究中，我们报告了 BikDD 与蛋白酶体抑制剂联合应用的潜在方法，这是基于我们的发现，即外源性表达的 BikDD 蛋白通过泛素依赖性和非依赖性途径发生蛋白酶体介导的降解。蛋白酶体抑制剂抑制可增加 BikDD 蛋白的稳定性，增强 BikDD 的凋亡作用。因此，高蛋白酶体活性可能是 BikDD 基因治疗中内在和获得性耐药发生的机制，与当前临床批准的蛋白酶体抑制剂联合治疗可能克服耐药性。
