Synergistic tumor suppression by coexpression of FUS1 and p53 is associated with down-regulation of murine double minute-2 and activation of the apoptotic protease-activating factor 1-dependent apoptotic pathway in human non-small cell lung cancer cells
Synergistic tumor suppression by coexpression of FUS1 and p53 is associated with down-regulation of murine double minute-2 and activation of the apoptotic protease-activating factor 1-dependent apoptotic pathway in human non-small cell lung cancer cells
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DOI：
10.1158/0008-5472.can-06-3463
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发表时间：
2007-01-15
期刊：
影响因子：
11.2
通讯作者：
Ji, Lin
中科院分区：
文献类型：
--
作者：
Deng, Wu-Guo;Kawashima, Hiroyaki;Ji, Lin
FUS1是在人类染色体3p21.3区域发现的一个新的肿瘤抑制基因。在大多数人类肺癌中发现了FUS1蛋白的表达缺失和翻译后修饰缺陷。野生型FUS1在3p21.3缺失的人肺癌细胞中的修复在体内外表现出强大的肿瘤抑制作用。在本研究中，我们评估了FUS1和抑癌基因P53的联合抗肿瘤活性，并探讨了它们在人非小细胞肺癌(NSCLC)细胞中相互作用的分子机制。我们发现N-[1-(2，3-二油酰氧基)丙基]-NNN-三甲基硫酸酯：胆固醇纳米颗粒介导的基因转移共表达FUS1和P53在体外显著抑制NSCLC细胞的生长并诱导其凋亡。我们还发现，FUS1和P53纳米颗粒的联合系统治疗协同抑制了人类H322肺癌原位小鼠模型中肿瘤的发展和生长。此外，我们发现，FUS1和P53的协同抑瘤作用与FUS1介导的小鼠双分钟2(MDM2)表达下调、P53蛋白积聚和稳定以及激活依赖于凋亡蛋白激活因子1(APAF-1)的凋亡途径一致。因此，我们的结果为FUS1介导的肿瘤抑制活性的分子机制提供了新的见解，并暗示结合两个或更多功能协同的肿瘤抑制基因的分子治疗可能构成一种新的有效的癌症治疗策略。
FUS1 is a novel tumor suppressor gene identified in human chromosome 3p21.3 region. Loss of expression and deficiency of posttranslational modification of FUS1 protein have been found in a majority of human lung cancers. Restoration of wild-type FUS1 in 3p21.3-deficient human lung cancer cells exhibited a potent tumor suppression function in vitro and in vivo. In this study, we evaluated the combined effects of FUS1 and tumor suppressor p53 on antitumor activity and explored the molecular mechanisms of their mutual actions in human non-small cell lung cancer (NSCLC) cells. We found that coexpression of FUS1 and P53 by N-[1-(2,3-dioleoyloxyl) propyl]-NNN-trimethylammoniummethyl sulfate:cholesterol nanoparticle-mediated gene transfer significantly and synergistically inhibited NSCLC cell growth and induced apoptosis in vitro. We also found that a systemic treatment with a combination of FUS1 and p53 nanoparticles synergistically suppressed the development and growth of tumors in a human H322 lung cancer orthotopic mouse model. Furthermore, we showed that the observed synergistic tumor suppression by FUS1 and p53 concurred with the FUS1-mediated down-regulation of murine double minute-2 (MDM2) expression, the accumulation and stabilization of p53 protein, as well as the activation of the apoptotic protease-activating factor 1 (Apaf-1)-dependent apoptotic pathway in human NSCLC cells. Our results therefore provide new insights into the molecular mechanism of FUS1-mediated tumor suppression activity and imply that a molecular therapy combining two or more functionally synergistic tumor suppressors may constitute a novel and effective strategy for cancer treatment.