Development of PEA-15 using a potent non-viral vector for therapeutic application in breast cancer.
Development of PEA-15 using a potent non-viral vector for therapeutic application in breast cancer.
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DOI：
10.1016/j.canlet.2014.09.033
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发表时间：
2015-01-28
期刊：
影响因子：
9.7
通讯作者：
Xie X
中科院分区：
文献类型：
--
作者：
Xie X;Tang H;Pengliu;Kong Y;Wu M;Xiao X;Yang L;Gao J;Wei W;Lee J;Bartholomeusz C;Ueno NT;Xie X
晚期乳腺癌需要系统治疗，因此迫切需要制定有效和安全的策略。为了确保靶向治疗的成功，我们开发了由人端粒酶逆转录酶（hTERT; T）启动子和多功能转基因扩增载体VISA（VP 16-GAL 4-WPRE集成系统放大器）组成的乳腺癌特异性构建体（T-VISA），以靶向晚期乳腺肿瘤中的PEA-15（星形胶质细胞中富集的磷蛋白）。PEA-15含有一个死亡效应结构域，其在细胞质中隔离细胞外信号调节激酶（ERK），从而抑制细胞增殖并诱导细胞凋亡。发现T-VISA-PEA-15具有高度特异性，在乳腺癌细胞中选择性表达PEA-15，并在体外和体内诱导癌细胞杀伤而不影响正常细胞。此外，T-VISA-PEA-15与脂质体纳米颗粒结合的静脉内治疗在携带晚期乳腺肿瘤的小鼠中减弱了肿瘤生长并延长了存活期。重要的是，与巨细胞病毒（CMV）启动子相比，当PEA-15通过我们的T-VISA系统表达时，几乎没有严重的毒性。因此，我们的研究结果证明了一种有效的癌症靶向治疗，值得在根除晚期乳腺癌的临床试验中开发。
Advanced breast cancer requires systemic treatment, therefore developing an efficient and safe strategy is urgently needed. To ensure the success of target therapy, we have developed a breast cancer-specific construct (T-VISA) composed of the human telomerase reverse transcriptase (hTERT; T) promoter and a versatile transgene amplification vector VISA (VP16-GAL4-WPRE integrated systemic amplifier) to target PEA-15 (Phosphoprotein enriched in astrocytes) in advanced breast tumors. PEA-15 contains a death effector domain that sequesters extracellular signal-regulated kinase (ERK) in cytoplasm, thereby inhibiting cell proliferation and inducing apoptosis. T-VISA-PEA-15 was found to be highly specific, selectively express PEA-15 in breast cancer cells, and induce cancer-cell killing in vitro and in vivo without affecting normal cells. Moreover, intravenously treatment with T-VISA-PEA-15 coupled with liposome nanoparticles attenuated tumor growth and prolonged survival in mice bearing advanced breast tumors. Importantly, there was virtually no severe toxicity when PEA-15 is expressed by our T-VISA system compared with cytomegalovirus (CMV) promoter. Thus, our findings demonstrate an effective cancer-targeted therapy that is worthy of development in clinical trials eradicating advanced breast cancer.