Nucleolin on the Cell Surface as a New Molecular Target for Gastric Cancer Treatment
Nucleolin on the Cell Surface as a New Molecular Target for Gastric Cancer Treatment
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DOI：
10.1248/bpb.33.796
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发表时间：
2010-05-01
影响因子：
2
通讯作者：
Suganuma, Masami
中科院分区：
文献类型：
--
作者：
Watanabe, Tatsuro;Hirano, Kazuya;Suganuma, Masami
核仁素是核仁中发现的丰富的非核糖体蛋白，并且是银染核仁组成区（AgNOR）的主要组分，AgNOR是癌症的组织病理学标志物，其在癌细胞中高度升高。我们最近报道了小鼠胃癌细胞表面的核仁素作为幽门螺杆菌新的致癌因子肿瘤坏死因子α诱导蛋白（Tip α）的受体。在本研究中，我们首先通过细胞分级分离和流式细胞术检测了核仁素在五种胃癌细胞系细胞表面的定位：我们发现核仁素大量存在于MKN-45、KATO III、MKN-74和AGS细胞表面，而MKN-1细胞表面的核仁素较少。小鼠腺胃正常上皮细胞的膜部分不含太多的核仁素，这表明核仁素易位到细胞表面发生在癌变过程中，使更容易与Tip α结合。AS 1411是一种核仁素靶向DNA适体，其抑制胃癌细胞系生长的效力顺序为：MKN-45>KATOIII>AGS>MKN-74=MKN-1，与诱导S期细胞周期停滞相关。基于细胞表面核仁素的不同量，异硫氰酸异黄绿素（FITC）-AS 1411更快地掺入MKN-45和AGS中而不是MKN-1细胞中。我们认为AS 1411首先与细胞表面的核仁素结合，然后结合复合物被掺入细胞。这些结果表明，细胞表面核仁素是一个新的和有前途的治疗胃癌的治疗靶点。
Nucleolin is an abundant non-ribosomal protein found in nucleolus and a major component of silver-stained nucleolar organizer region (AgNOR), a histopathological marker of cancer which is highly elevated in cancer cells. We recently reported that nucleolin on the cell surface of mouse gastric cancer cells acts as a receptor for tumor necrosis factor-alpha-inducing protein (Tip alpha), a new carcinogenic factor of Helicobacter pylori. In this study, we first examined the localization of nucleolin on cell surface of five gastric cancer cell lines by cell fractionation and flow cytometry: We found that large amounts of nucleolin were present on surface of MKN-45, KATOIII, MKN-74, and AGS cells, with smaller amounts on surface of MKN-1 cells. The membrane fraction of normal epithelial cells of mouse glandular stomach did not contain much nucleolin, suggesting that translocation of nucleolin to the cell surface occurs during carcinogenesis, making for easier binding with Tip alpha. AS1411, a nucleolin targeted DNA aptamer, inhibited growth of gastric cancer cell lines in this order of potency: MKN-45>KATOIII>AGS>MKN-74=MKN-1, associated with induction of S-phase cell cycle arrest. Fluorescein isothiocyanate (FITC)-AS1411 was more rapidly incorporated into MKN-45 and AGS than into MKN-1 cells, based on varying amounts of cell surface nucleolin. We think that AS1411 first binds to nucleolin on the cell surface and that the binding complex is then incorporated into the cells. All results indicate that nucleolin on the cell surface is a new and promising therapeutic target for treatment of gastric cancer.