Analysis of PI3K signal transduction and target therapy of PI3Kp85 by PR-39 analog for hepatocellular carcinoma

PR-39类似物PI3Kp85信号转导分析及靶向治疗肝细胞癌

• 批准号: 14570439
• 负责人: WATARI Jiro
• 金额: $ 2.43万
• 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: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570439/
• 关键词: Endogenous antimicrobial peptide; Target therapy; Hepatocellular carcinoma

PR-39 is a mammalian endogenous antibiotic, which works as the effecter molecule of innate immunity, induces the synthesis of syndecan-1, a transmembrane heparin sulphate proteoglycan involved in cell-to matrix interactions and skin wound healing. Previously we revealed that the expression of syndecan-1 was reduced in human hepatocellular carcinomas with high metastatic potential (Matsumoto, Int J Cancer,1997). Gene transduction of syndecan-1 inhibits the invasion activity in hepatoma cell lines. Furthermore gene transduction of PR-39, which is inducer for syndecan-1, inhibits the invasion activity and suppresses the motile activity in addition to the disorganization of action structure (Ohtake, Br J Cancer,1999).PR-39 has five repeats of the praline-rich motif ; PXXPPXXP, which has an ability to bind to Src homology 3 (SH3) domains. PR-39 actually binds to SH3 domains of p47^<phox> and p130^<Cas>. To determine the target molecule of PR-39 in intracellular signal transduction pathway, … More we transfected PR-39 gene into the fibroblasts which had already been transformed with activated k-ras. The PR-39 gene transfectant showed reorganization of actin structure, suppression of cell proliferation and decrease of mitogen-activated protein (MAP) kinase activity PR-39 binds to PI3-kinase p85α, which is a regulatory subunit of PI3-kinase and one of the effectors by which ras induces cytoskeletal changes and stimulates mitogenesis. So our data suggest that PR-39 alters actin structure and cell proliferation by binding to PI3-kinase p85α (Tanaka, Jpn J Cancer Res,2001).Furthermore, we investigated with anti-cancer effect of PR-39 against mouse colon cancer cell line, colo26, which revealed cachexia using the mouse model of subcutaneous tumor transplantation. There was no effect for suppression of tumor growth in both the mice which have intra-pentoneal load of synthetic peptide of PR-39, and PR-39 transgenic mice, which were subcutaneously transplanted with colo26. Either not in the mice which were subcutaneously transplanted with colo26, which had been transfected with PR-39. However, the survival period of only the mice which carried PR-39 transfectants extended as compared with the control. Our data suggest that PR-39 gene transduction may improve cachexia and extend survival period. Less

PR-39是一种哺乳动物内源性抗生素，作为先天免疫的效应分子，诱导syndecan-1的合成，syndecan-1是一种跨膜硫酸肝素蛋白多糖，参与细胞-基质相互作用和皮肤伤口愈合。先前我们发现syndecan-1在具有高转移潜力的人肝细胞癌中表达降低（Matsumoto, Int J Cancer,1997）。syndecan-1基因转导抑制肝癌细胞系的侵袭活性。此外，作为syndecan-1的诱导剂PR-39的基因转导，除了破坏作用结构外，还抑制了侵袭活性和运动活性（Ohtake, Br J Cancer,1999）。PR-39有5个富含果仁氨酸的基序重复；PXXPPXXP，能够结合Src同源3 （SH3）结构域。PR-39实际上结合到p47^<phox>和p130^<Cas>的SH3结构域。为了确定PR-39在细胞内信号转导通路中的靶分子，我们将PR-39基因转染到已被活化的k-ras转化的成纤维细胞中。PR-39基因转染后表现为肌动蛋白结构重组、细胞增殖抑制和丝裂原活化蛋白（MAP）激酶活性降低。PR-39与pi3激酶的调控亚基p85α结合，p85α是ras诱导细胞骨架变化和刺激有丝分裂发生的效应物之一。因此，我们的数据表明PR-39通过结合pi3激酶p85α改变肌动蛋白结构和细胞增殖（Tanaka, Jpn J Cancer Res,2001）。此外，我们还利用小鼠皮下肿瘤移植模型研究了PR-39对小鼠结肠癌细胞株col26的抗癌作用，该细胞株显示恶病质。在pentoneal内负荷PR-39合成肽的小鼠和皮下移植的PR-39转基因小鼠均无抑制肿瘤生长的作用。对经PR-39转染的小鼠皮下移植大肠杆菌26也无明显影响。然而，只有携带PR-39基因的小鼠存活时间较对照组延长。我们的数据表明PR-39基因转导可能改善恶病质，延长生存期。少