Elucidation of the roles of Pim-1 induced under hypoxia in pancreatic cancer and its application to the cancer therapy

阐明缺氧诱导的Pim-1在胰腺癌中的作用及其在癌症治疗中的应用

基本信息

批准号：
16390202
负责人：
KOBAYASHI Masanobu
金额：
$ 9.28万
依托单位：
Hokkaido University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
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/grant/KAKENHI-PROJECT-16390202/
关键词：
Pim-1 hypoxia apoptosis resistance to anticancer drugs in vivo growth 膵がん癌遺伝子 PIM-1

项目摘要

In this study, we examined whether the inhibition of Pim-1 activity, is effective treatment pancreatic cancer, based on the findings that Pim-1 protein expression enhanced under hypoxic conditions. According to the previous reports demonstrating that the protein fused to polypeptides composed of eleven arginine can pass through the cytoplasmic membrane, we constructed an expression vector encoding 11 arginine-signal sequence of Thrombopoietin-dominant negative Pim-1 protein. PCI-43. cells, a pancreatic cancer cell line, were inoculated subcutaneously into the back of SCID mice. Then the mice were treated with the injection of the vectors into the femoral muscle. At 21 days after the treatment, the tumors in the mice treated with the injection of dominant negative PIM-1 expression vector disappeared, whereas the tumors in those treated with empty vector grew. These results suggest that the gene therapy using dominant negative Pim-1 expression vector may be effective for the cancer. However, the doses of expression vector to inject should be reduced for clinical trials. We sought small chemical compound library for the chemical compounds which could suppress the function of Pim-1. We found fourteen small chemical compounds which suppressed the phosphorylation activity of PIM-1 by more than 40 %. We are now planning to examine the in vivo anti-tumor effects of those compounds.

在这项研究中，我们基于缺氧条件下 Pim-1 蛋白表达增强的发现，检验了抑制 Pim-1 活性是否能有效治疗胰腺癌。根据前人报道，与11个精氨酸组成的多肽融合的蛋白可以穿过细胞质膜，我们构建了编码11个精氨酸信号序列的血小板生成素显性阴性Pim-1蛋白的表达载体。 PCI-43。细胞，一种胰腺癌细胞系，被皮下接种到 SCID 小鼠的背部。然后将载体注射到股骨肌肉中来治疗小鼠。治疗后21天，注射显性失活PIM-1表达载体的小鼠中肿瘤消失，而注射空载体的小鼠中肿瘤生长。这些结果表明使用显性失活 Pim-1 表达载体的基因治疗可能对癌症有效。但临床试验时应减少表达载体的注射剂量。我们寻找可以抑制Pim-1功能的化合物的小型化合物库。我们发现 14 种小化合物可以抑制 PIM-1 的磷酸化活性超过 40%。我们现在计划检查这些化合物的体内抗肿瘤作用。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rapid degradation of CDtl upon UV-induced DNA damage is mediated by SCF^<Skp2> complex.

CDtl在UV诱导的DNA损伤后的快速降解是由SCF^<Skp2>复合物介导的。

DOI：
发表时间：
2004
期刊：
J Biol Chem 279
影响因子：
0
作者：
成瀬達;石黒洋;成瀬達;成瀬達;Okada F;Okada F;Miseki T;Okada F et al.;Kakinuma Y;Suzuki A;Zhao W;Matsuda N et al.;Kakinuma Y et al.;Suzuki A et al.;Zhai W et al.;Yoshihiko Kakinuma;Eiko Hayashi;Junji Tanaka;Fumihiro Higashino;Kondo T
通讯作者：
Kondo T

Prevention of inflammation-mediated acquisition of metastatic properties of benign mouse fibrosarcoma cells by administration of an orally available SOD.

通过口服 SOD 来预防炎症介导的良性小鼠纤维肉瘤细胞的转移特性。

DOI：
发表时间：
2006
期刊：
Br J Cancer 94
影响因子：
0
作者：
成瀬達;石黒洋;成瀬達;成瀬達;Okada F
通讯作者：
Okada F

Hypoxia suppresses the production of matrix metalloprote-inases and the migration of human monocyte-derived dentritic cells.

缺氧会抑制基质金属蛋白酶的产生和人单核细胞衍生的树突细胞的迁移。

DOI：
发表时间：
2005
期刊：
Eur J Immunol 35
影响因子：
0
作者：
成瀬達;石黒洋;成瀬達;成瀬達;Okada F;Okada F;Miseki T;Okada F et al.;Kakinuma Y;Suzuki A;Zhao W
通讯作者：
Zhao W

Cytolytic activity and regulatory functions of inhibitory NK cell receptor-expressing T cells expanded from peripheral blood mononuclear cells.

表达抑制性 NK 细胞受体的 T 细胞从外周血单核细胞扩增而来的溶细胞活性和调节功能。

DOI：
发表时间：
2004
期刊：
Blood 104
影响因子：
0
作者：
Wang;JQ.;Kon;J.;Mogi;C.;Tobo;M.;Damirin;A.;Sato;K.;Komachi;M.;Malchinkhuu;E.;Murata;N.;Kimura;T.;Kuwabara;A.;Wakamatsu;K.;Koizumi;T.;Uede;T.;Tsujimoto;G.;Kurose;H.;Sato;T.;Harada;A.;Misawa;N.;Tomura;H.;Okajima;F.;Takaku H;Takaku H;Matsuda N;Koike T;Kondo K;Tanaka J
通讯作者：
Tanaka J

The role of NADPH oxidase-derived reactive oxygen species in the acquisition of metastatic ability of tumor cells.

NADPH氧化酶衍生的活性氧在肿瘤细胞获得转移能力中的作用。