Specific growth suppression of human cancer cells by targeted delivery of Dictyostelium mitochondrial ribosomal protein S4.
Specific growth suppression of human cancer cells by targeted delivery of Dictyostelium mitochondrial ribosomal protein S4.
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DOI：
10.1186/1475-2867-14-56
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发表时间：
2014
影响因子：
5.8
通讯作者：
Maeda Y
中科院分区：
文献类型：
--
作者：
Chida J;Araki H;Maeda Y
一般来说，生长和分化是相互排斥的，但在整个发育过程中相互协作调节。因此，细胞从生长转向分化的过程不仅对于生物体的发育非常重要，而且对于恶性转化也非常重要，在恶性转化中，该过程被逆转。我们之前使用盘基网柄菌模型系统证明，盘基网柄菌线粒体核糖体蛋白S4（Dd-mrp4）基因表达对于细胞分化的启动至关重要：Dd-mrp4缺失的细胞无法启动分化，而在线粒体外细胞质中过表达Dd-mrp4的mrp4OE细胞中，细胞分化的初始步骤和随后的形态发生显着增强。这提出了一种可能性，即人类细胞中 Dd-mrp4 的异位强制表达可能通过诱导细胞分化来抑制其生长，特别是恶性肿瘤细胞的生长。三种载体构建体（空载体：pcDNA3.1（Mock）；带有盘基网柄菌胞质核糖体蛋白S4的pcDNA3.1-rps4；带有盘基网柄菌线粒体核糖体蛋白S4的pcDNA3.1-mrp4）转染四种人肿瘤细胞系。作为对照，四种人类原代培养细胞同样被上述载体构建体转染。转染后，使用细胞活力测定分析细胞的生长动力学，并使用TUNEL法评价细胞凋亡。异位表达的 Dd-mrp4 通过诱导细胞凋亡来抑制细胞增殖，特别是在人肺腺癌 (A549)、上皮性宫颈癌 (HeLa)、肝细胞癌 (HepG2) 和结肠癌 (Caco-2) 中，但在原代培养的正常细胞中则不然，例如人脑微血管内皮细胞 (HBMEC)；人脐静脉内皮细胞 (HUVEC) 和人正常肝细胞 (hHeps™)，但有一个例外（人心脏成纤维细胞 (HCF)）。目前发现，Dd-mrp4 在人类几种肿瘤细胞系中的异位强制表达特异性抑制其增殖，强烈表明源自盘基网柄菌线粒体的 Dd-mrp4 基因可能为破坏人类癌症中的细胞活力途径提供一种新的有前景的治疗策略。
In general, growth and differentiation are mutually exclusive but are cooperatively regulated throughout development. Thus, the process of a cell’s switching from growth to differentiation is of great importance not only for the development of organisms but also for malignant transformation, in which this process is reversed. We have previously demonstrated using a Dictyostelium model system that the Dictyostelium mitochondrial ribosomal protein S4 (Dd-mrp4) gene expression is essential for the initiation of cell differentiation: Dd-mrp4-null cells fail to initiate differentiation, while the initial step of cell differentiation and the subsequent morphogenesis are markedly enhanced in mrp4OE cells overexpressing the Dd-mrp4 in the extramitochondrial cytoplasm. This raised a possibility that the ectopically enforced expression of the Dd-mrp4 in human cells might inhibit their growth, particularly of malignant tumor cells, by inducing cell differentiation. Four kinds of human tumor cell lines were transfected by three kind of vector constructs (the empty vector: pcDNA3.1 (Mock); pcDNA3.1-rps4 bearing Dictyostelium cytoplasmic ribosomal protein S4; pcDNA3.1-mrp4 bearing Dictyostelium mitochondrial ribosomal protein S4). As controls, four kinds of human primary cultured cells were similarly transfected by the above vector constructs. After transfection, growth kinetics of cells was analyzed using cell viability assay, and also the TUNEL method was used for evaluation of apoptotic cells. Ectopically expressed Dd-mrp4 suppressed cell proliferation through inducing apoptotic cell death specifically in the human lung adenocarcinoma (A549), epithelial cervical cancer (HeLa), hepatocellular carcinoma (HepG2) and colonic carcinoma (Caco-2), but not in primary cultured normal cells, such as human brain microvascular endothelial cells (HBMECs); human umbilical vein endothelial cells (HUVECs) and human normal hepatocytes (hHeps™), with one exception (human cardiac fibloblasts (HCF)). The present finding that the ectopically enforced expression of Dd-mrp4 in human several tumor cell lines specifically suppresses their proliferation suggests strongly that the Dd-mrp4 gene derived from Dictyostelium mitochondria may provide a new promising therapeutic strategy for disrupting cell viability pathways in human cancers.
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DOI：
10.18632/aging.100459
发表时间：
2012-05
期刊：
Aging
影响因子：
--
作者：
Favaloro B;Allocati N;Graziano V;Di Ilio C;De Laurenzi V
通讯作者：
De Laurenzi V
影响因子：
2.7
作者：
Kotsifas, M;Barth, C;Fisher, PR
通讯作者：
Fisher, PR
影响因子：
2.9
作者：
MAEDA, Y;OHMORI, T;AMAGAI, A
通讯作者：
AMAGAI, A
影响因子：
2.9
作者：
Matsuyama, SI;Maeda, Y
通讯作者：
Maeda, Y
影响因子：
37.8
作者：
Albrecht-Schgoer K;Schgoer W;Holfeld J;Theurl M;Wiedemann D;Steger C;Gupta R;Semsroth S;Fischer-Colbrie R;Beer AG;Stanzl U;Huber E;Misener S;Dejaco D;Kishore R;Pachinger O;Grimm M;Bonaros N;Kirchmair R
通讯作者：
Kirchmair R