Development of molecular targeting drugs for anti-metastasis and anti-drug resistance of tumor cells

肿瘤细胞抗转移、抗耐药性分子靶向药物开发

• 批准号: 16590067
• 负责人: ITO Akira
• 金额: $ 2.24万
• 依托单位: Tokyo University of Pharmacy and Life Sciences
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590067/
• 关键词: tumor; metastasis and invasion; P-glycoprotein; EMMPRIN; MMP-1; collagenase-1; hinge-region; nobiletin; triptolide; ガン; EMMPRIN(エンプリン); collagenase-1; マトリックスメタロプロテアーゼ(MMP); コラゲナーゼ; SKG-II細胞

Extracellular matrix metalloproteinase inducer (EMMPRIN)/CD147 is highly expressed on the cell surface of various tumors, and closely participates in the tumor cell invasion by augmenting matrix metalloproteinase (MMP) production. In addition to the MMP-inducible activity, the cell surface EMMPRIN binds to proMMP-1/collagenase-1 on human lung carcinoma cells and human endometrium, but the significance of EMMPRIN-MMP-1 complex has not been clarified. In the present study, we clarified that EMMPRIN bind to both proMMP-1 and active MMP-1, but not other MMPs including MMPs-2, -3, and -13 on human uterine cervical carcinoma SKG-II cells. This binding was effectively interfered by a chimera protein of which hinge region was substituted by that of MMP-13, indicating that the hinge region of MMP-1 was essential for MMP-1 binding to EMMPRIN. The proMMP-1 bound to EMMPRIN was activated by plasmin, an activator of proMMPs. When the active MMP-1 bound to cell surface of SKG-II cells via EMMPRIN, the invasive activity of cells through type I-collagen gel was enhanced as compared control and proMMP-1 bound cells. The hinge region of peptide (17 mer) of MMP-1 effectively interfered with the binding of active MMP-1 as well as proMMP-1 to SKG-II cells and their type I collagen gel invasive activity. Therefore EMMPRIN is closely participates in the cancer cell invasion by forming MMP-1-EMMPRIN complex as well as induction of proMMPs. In addition, the hinge region peptide may be a useful tool for interfering with the function of MMP-1-EMMPRIN.

细胞外基质金属蛋白酶诱导因子（EMMPRIN）/CD 147在多种肿瘤细胞表面高度表达，通过促进基质金属蛋白酶（MMP）的产生，与肿瘤细胞的侵袭密切相关。除了MMP诱导活性外，细胞表面EMMPRIN与人肺癌细胞和人子宫内膜上的proMMP-1/胶原酶-1结合，但EMMPRIN-MMP-1复合物的意义尚未阐明。在本研究中，我们阐明了EMMPRIN结合proMMP-1和活性MMP-1，但不结合其他MMPs，包括MMPs-2，-3，和-13人宫颈癌SKG-II细胞。这种结合有效地干扰嵌合体蛋白的铰链区被替换的MMP-13，表明MMP-1的铰链区是必不可少的MMP-1结合EMMPRIN。与EMMPRIN结合的proMMP-1被proMMP的激活剂纤溶酶激活。当活性MMP-1通过EMMPRIN结合到SKG-II细胞的细胞表面时，细胞通过I型胶原凝胶的侵袭活性与对照和proMMP-1结合的细胞相比增强。MMP-1的多肽铰链区（17 mer）有效地干扰活性MMP-1以及proMMP-1与SKG-II细胞的结合及其I型胶原凝胶侵袭活性。因此，EMMPRIN通过形成MMP-1-EMMPRIN复合物以及诱导proMMPs而密切参与癌细胞侵袭。此外，铰链区肽可能是干扰MMP-1-EMMPRIN功能的有用工具。

项目成果

Triptolide, a deterpenoid triepoxide, induces anti-tumor proliferation via activation of c-JUN nh2 terminal kinase 1 by decreasing phosphatidylionsitol 3-kinase activity in human tumor cells

Triptolide 是一种萜类三环氧化物，通过降低人肿瘤细胞中的磷脂酰肌醇 3 激酶活性，激活 c-JUN nh2 末端激酶 1，从而诱导抗肿瘤增殖

• 发表时间: 2005
• 期刊: Biochemical and Biophysical Research Communications 336(4)
• 作者: Gotoh;M. et al.;今井浩孝(共著);Yoshiki Miyata
• 通讯作者: Yoshiki Miyata

特許権

专利权

• 发表时间: 2018

臨床腫瘍内科学入門

临床肿瘤学导论

• 发表时间: 2005
• 作者: Yamagami W;Banno K;et al.;金倉 譲
• 通讯作者: 金倉 譲

Triptolide, a deterpenoid triepoxide, induces anti-tumor proliferation via activation of c-JUN NH2 terminal kinase 1 by decreasing phosphatidylinositol 3-kinase activity in human tumor cells

Triptolide 是一种萜类三环氧化物，通过降低人类肿瘤细胞中的磷脂酰肌醇 3 激酶活性，激活 c-JUN NH2 末端激酶 1，从而诱导抗肿瘤增殖

• 发表时间: 2005
• 期刊: Biochemical and Biophysical Research Communications 336(4)
• 作者: Yoshiki Miyata;Takashi Sato;Akira Ito
• 通讯作者: Akira Ito

マトリックスメタロプロテアーゼと疾病

基质金属蛋白酶和疾病

• 发表时间: 2005
• 期刊: 日本眼薬理学会誌 19(1)
• 作者: Hatada;S. et al.;今田 啓介
• 通讯作者: 今田 啓介