Mechanism of inhibitory effect of protein C inhibitor on tumorigenesis and angiogenesis

Protein C抑制剂抑制肿瘤发生和血管生成的机制

• 批准号: 18591749
• 负责人: HAYASHI Tatsuya
• 金额: $ 2.55万
• 依托单位: Mie University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591749/
• 关键词: protein C inhibitor; angiogenesis; serine protease inhibitor; VEGF; heparin; MAPK; 腎癌; 浸潤; 転移; 反応部位

Protein C inhibitor(PCI), which belongs to serine protease inhibitor(SERPIN) family, regulates the anticoagulant protein C pathway and also inhibits urinary plasminogen activator(uPA), a mediator of tumor cell invasion. PCI can bind to heparin, and inhibition of these proteases by PCI is accelerated in the presence of heparin. In the present study, we evaluated the effect of human PCI and its inactive derivatives on tumor growth, metastasis and angiogenesis. The invasiveness of MDA-231 cells was inhibited by recombinant intact PCI, but not by reactive site-modified PCI(R354APCI) or by the N-terminal fragment of protease-cleaved PCI(NTPCI). The in vitro invasiveness of MDA-231 cells expressing intact PCI(MDA-PCI) was also significantly decreased as compared to MDA-231 cells expressing R354APCI(MDA-R354APCI) or NTPCI(MDA-NTPCI). Further, in vivo growth and metastatic potential of MDA-PCI, MDA-R354APCI and MDA-NTPCI cells in severe combined immunodeficient(SCID) mice were significantly decreased as compared to MDA-Mock cells. Angiogenesis was also significantly decreased in Matrigel implant containing MDA-PCI, MDA-R354APCI or MDA-NTPCI cells as compared to that containing MDA-Mock cells. In vivo angiogenesis in rat cornea and in vitro tube formation were also inhibited by recombinant intact PCI, R354APCI and NTPCI. Furthermore, the anti-angiogenic, activity was strong as cleaved antithrombin and pigment epithelium-derived factor. Subsequently, we examined the effect of PCI on vascular endothelial growth factor(VEGF) -induced activation of mitogen-activated protein kinase(MAPK) in the presence or absence of heparin using Western- blot analysis, and suggests that MAPK activation is inhibited by PCI only in the presence of heparin.Overall, this study showed that, PCI inhibits angiogenesis independently of its protease inhibitory activity by inhibiting MAPK activation, and heparin-binding site on PCI is important for exerting its anti-angiogenic activity

属于丝氨酸蛋白酶抑制剂（SERPIN）家族的蛋白C抑制剂（PCI）调节抗凝蛋白C途径，并抑制肿瘤细胞侵入介质的尿纤溶酶原激活剂（UPA）。 PCI可以与肝素结合，并且在存在肝素的情况下通过PCI抑制这些蛋白酶。在本研究中，我们评估了人类PCI及其无效衍生物对肿瘤生长，转移和血管生成的影响。重组完整的PCI抑制了MDA-231细胞的侵入性，而不是通过反应性位点修饰的PCI（R354APCI）或蛋白酶裂解的PCI（NTPCI）的N端片段来抑制。与表达R354APCI（MDA-R354APCI）或NTPCI（MDA-NTPCI）的MDA-231细胞相比，表达完整PCI（MDA-PCI）的MDA-231细胞的体外侵入性也显着降低。此外，与MDA-Mock细胞相比，严重合并免疫缺陷型（SCID）小鼠中MDA-PCI，MDA-R354APCI和MDA-NTPCI细胞的体内生长和转移潜力显着降低。与含有MDA莫克细胞的含有MDA-PCI，MDA-R354APCI或MDA-NTPCI细胞的母质植入物中，血管生成也显着降低。重组完整的PCI，R354APCI和NTPCI也抑制了大鼠角膜和体外管形成的体内血管生成。此外，抗血管生成的活性是裂解的抗凝血酶和色素上皮源性因子的强大。 Subsequently, we examined the effect of PCI on vascular endothelial growth factor(VEGF) -induced activation of mitogen-activated protein kinase(MAPK) in the presence or absence of heparin using Western- blot analysis, and suggests that MAPK activation is inhibited by PCI only in the presence of heparin.Overall, this study showed that, PCI inhibits angiogenesis independently of its protease inhibitory activity by抑制PCI上的MAPK激活和肝素结合位点对于发挥其抗血管生成活性很重要

项目成果

Protein C and its inhibitor in malignancy

• DOI: 10.1055/s-2007-991534
• 发表时间: 2007-10-01
• 期刊: SEMINARS IN THROMBOSIS AND HEMOSTASIS
• 影响因子: 5.7
• 作者: Suzuki, Koji;Hayashi, Tatsuya
• 通讯作者: Hayashi, Tatsuya

Lipopolysaccharide-induced decreased protein S expression in liver cells is mediated by MEK/ERK signaling and NFkB activation : involvement of membrane-bound CD14 and toll-like receptor-4

脂多糖诱导的肝细胞中蛋白 S 表达下降是由 MEK/ERK 信号传导和 NFkB 激活介导的：膜结合 CD14 和 Toll 样受体 4 的参与

• 发表时间: 2006
• 期刊: J Thromb Haemost 4
• 作者: Hayashi;T;Kishiwada;M;Fujii;K;Yuasa;H;Nishioka;J;Ido;M;Gabazza;EC;Suzuki;K
• 通讯作者: K

Differential regulation of protein S expression in hepatocytes and sinusoidal endothelial cells in rats with cirrhosis

• DOI: 10.1111/j.1538-7836.2006.02227.x
• 发表时间: 2006-12-01
• 期刊: JOURNAL OF THROMBOSIS AND HAEMOSTASIS
• 影响因子: 10.4
• 作者: Fujii, K.;Kishiwada, M.;Suzuki, K.
• 通讯作者: Suzuki, K.

プロテインCインヒビター(PCI)はヘパリン非依存性に肝細胞増殖因子活性化因子(HGFA)を阻害する

蛋白 C 抑制剂 (PCI) 以不依赖肝素的方式抑制肝细胞生长因子激活剂 (HGFA)

• 发表时间: 2007
• 作者: Nakahara;H;Gabazza;EC;Fujimoto;H;Nishii;Y;D'Alessandro-Gabazza;CN;Bruno;NE;Takagi;T;Hayashi;T;Maruyama;J;Maruyama;K;Imanaka-Yoshida;K;Suzuki;K;Yoshida;T;Adachi;Y;Taguchi;O;Hayashi T;林 辰弥;林 辰弥
• 通讯作者: 林 辰弥

「研究成果報告書概要(和文)」より

摘自《研究结果报告摘要（日文）》

• 发表时间: 2005
• 作者: Kawauchi;et. al.;Nishimura et al.;Dezawa et al.;Yoshizawa et al.;星野 幹雄;星野 幹雄
• 通讯作者: 星野 幹雄