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prline-rich endogenous antimicrobial peptide suppresses colon carcinoma cell proliferation by adaptor molecule competition

富含脯氨酸的内源性抗菌肽通过接头分子竞争抑制结肠癌细胞增殖

基本信息

批准号：
12670452
负责人：
FUJIMOTO Yoshinori
金额：
$ 2.24万
依托单位：
Asahikawa Medical College
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670452/
关键词：
antimicrobial peptide PR-39 syndecan actin signal transduction colon carcinoma PI3 Kinase PI3 Kinase K-ras

项目摘要

PR-39, which is an endogenous antimicrobial peptide, can bind to Src homology 3 domains of the NADPH complex protein p47phox and the signaling adapter protein p130Cas. Recently, we have reported that PR-39, gene transduction altered invasive activity and actin structure on human hepatocellular carcinoma cells, suggesting that this peptide affects cellular signaling pathway due to its proline-rich motif. In order to clarify the mechanism of the PR-39 functions, we transfected with PR-39 gene into mouse NIH3T3 cells which were already transformed with human activated k-ras gene. The PR-39 gene transfectant showed a reorganization of actin structure and suppression of cell proliferation both in vitro and in vivo. Co-immunoprecipitation analysis revealed that the PR-39 binds to PI3-kinase p85a, which is a regulatory subunit of PI3-kinase and one of the effectors by which ras induces cytoskeletal changes and stimulates the mitogenesis. PI3-kinase activity of the PR-39 gene transfectant was decreased compared with that of the ras transformant. These results suggest that the PR-39 alters actin structure and cell proliferation rate by binding to PI3-kinase p85a and suppressing the PI3-kinase activity, The PR-39 gene transfectant derived from colon carcinoma cells also showed the morphological change and the suppression of the proliferation in vitro and vivo, suggesting that PR-39 might be a candidate for the targeting therapy of cancers.

PR-39是一种内源性抗菌肽，可与NADPH复合蛋白p47 phox和信号衔接蛋白p130 Cas的Src同源3结构域结合。最近，我们报道了PR-39基因转导改变了人肝癌细胞的侵袭活性和肌动蛋白结构，表明该肽由于其富含脯氨酸的基序而影响细胞信号传导途径。为了阐明PR-39的作用机制，我们将PR-39基因转染到已经转化了人活化的k-ras基因的小鼠NIH 3 T3细胞中。PR-39基因转染细胞在体内外均表现出肌动蛋白结构的重组和细胞增殖的抑制。免疫共沉淀分析显示PR-39与PI 3-kinase p85 a结合，p85 a是PI 3-kinase的调节亚基，是ras诱导细胞骨架变化和刺激有丝分裂的效应子之一。PR-39基因转染组的PI 3-激酶活性较ras基因转染组明显降低。这些结果表明PR-39通过与PI 3-kinase p85 a结合，抑制PI 3-kinase活性，从而改变肌动蛋白结构和细胞增殖速率。PR-39基因转染的结肠癌细胞在体内外均表现出形态学改变和细胞增殖抑制，提示PR-39有可能成为肿瘤靶向治疗的候选药物。