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聚糖，参与细胞与基质的相互作用和皮肤伤口愈合。 syndecan-1 在具有高转移潜力的人肝细胞癌中减少（Matsumoto，Int J Cancer，1997） syndecan-1 的基因转导。此外，作为 syndecan-1 诱导剂的 PR-39 的基因转导，除了作用结构的瓦解之外，还抑制侵袭活性并抑制运动活性（Ohtake，Br J Cancer，1999）。 ).PR-39 具有 5 个富含脯氨酸基序的重复序列；PXXPPXXP，它能够与 PR-39 实际结合的 Src 同源性 3 (SH3) 结构域结合。 p47^<phox> 和 p130^<Cas> 的 SH3 结构域为了确定 PR-39 在细胞内信号转导途径中的靶分子，我们将 PR-39 基因转染到已经用活化 k 转化的成纤维细胞中。 -ras。PR-39 基因转染子表现出肌动蛋白结构的重组、细胞增殖的抑制以及丝裂原激活蛋白（MAP）激酶活性的降低。 PI3-激酶 p85α，它是 PI3-激酶的调节亚基，也是 ras 诱导细胞骨架变化并刺激有丝分裂的效应子之一，因此我们的数据表明 PR-39 通过与 PI3-激酶 p85α 结合来改变肌动蛋白结构和细胞增殖。 (Tanaka，Jpn J Cancer Res，2001)。此外，我们研究了PR-39对小鼠结肠癌的抗癌作用细胞系colo26，使用皮下肿瘤移植的小鼠模型显示恶病质。在腹膜内负载PR-39合成肽的小鼠和PR-39转基因小鼠中没有抑制肿瘤生长的效果。皮下移植colo26的小鼠没有转染PR-39的小鼠的存活期。 PR-39转染子与对照相比延长了寿命，我们的数据表明PR-39基因转导可以改善恶病质并延长存活期。