An N-terminal 78 amino acid truncation of REIC/Dkk-3 effectively induces apoptosis
An N-terminal 78 amino acid truncation of REIC/Dkk-3 effectively induces apoptosis
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DOI：
10.1016/j.bbrc.2008.08.079
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发表时间：
2008-10-31
影响因子：
3.1
通讯作者：
Kumon, Hiromi
中科院分区：
文献类型：
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作者：
Abarzua, Fernando;Kashiwakura, Yuji;Kumon, Hiromi
肿瘤抑制基因REIC/DKK-3的过表达通过内质网应激诱导癌细胞凋亡。因此，确定导致内质网应激的REIC/DKK-3部分可能对以REIC/DKK-3为基础的癌症治疗的发展至关重要。在这里，我们制作了几种截短形式的REIC/DKK-3，并研究了它们对前列腺癌的治疗潜力。在三种截短形式中，含有REIC/DKK-3((1-78)REIC/DKK-3)N端78个氨基酸区域的变异体在人前列腺癌细胞(PC3)中诱导内质网应激和细胞凋亡的作用最强。对于体内基因表达，我们将一种可生物降解的聚合物与裸DNA偶联，在PC3来源的皮下肿瘤中获得了强劲的转基因表达。在治疗实验中，我们证明了与对照组相比，多次直接注射聚合物偶联的1-78REIC/DKK-3质粒可引起内质网应激，并显著缩小皮下肿瘤体积。我们认为，这种非病毒策略可能是病毒基因治疗的有效替代方案。(C)2008 Elsevier Inc.保留所有权利。
Overexpression of REIC/Dkk-3 (a tumor suppressor gene) induces cancer cell apoptosis through endoplasmic reticulum (ER) stress. Therefore, the identification of the portion of REIC/Dkk-3 that causes ER stress may be essential for the development of cancer treatment based on REIC/Dkk-3. Here, we made several truncated forms of REIC/Dkk-3 and investigated their therapeutic potentials against prostate cancer. Among three truncated forms, a variant comprising the N-terminal 78 amino acid region of REIC/Dkk-3 ((1-78) REIC/Dkk-3) most strongly induced ER stress and apoptosis in human prostate cancer cells (PC3). For in vivo gene expression, we coupled a biodegradable polymer with naked DNA, which attained robust trans-gene expression in PC3-derived subcutaneous tumor. In therapeutic experiments, we demonstrated that multiple direct injections of polymer-conjugated 1-78REIC/Dkk-3 plasmid provoke ER stress and significantly reduced the subcutaneous tumor volume compared with the control group. We suggest this non-viral strategy may be an effective alternative to viral gene therapy. (C) 2008 Elsevier Inc. All rights reserved.