The Development of novel therapeutic strategy for anaplastic thyroid carcinoma by manipulating the ubiquitin-proteasome activity

通过操纵泛素蛋白酶体活性开发未变性甲状腺癌的新治疗策略

基本信息

批准号：
12671088
负责人：
TANIGUCHI Shin-ichi
金额：
$ 2.18万
依托单位：
Tottori University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671088/
关键词：
UBIQUITIN PROTEASOME ANAPLASTIC CARCINOMA THYROID プロテアソーム活性化因子 Tet onシステム

项目摘要

Anaplastic thyroid carcinoma is a poorly differentiated carcinoma found in elderly people. The patients with anaplastic carcinoma always suffer from poor prognosis. It is an urgent business to develop the effective strategy to suppress the growth of anaplastic carcinoma and prolong the prognosis of patients. We focused on the ubiqitin-proteasome system. Proteasome is a major intracellular proteinase found as a large protein complex composed of at least 14 distinct but homologous subunits with molecular masses of 21-32 kD and they are assembled into an approximately 700 kDa cylindcal structure. It is involved in the destruction of regulatory proteins responsible for biological processes such as cell cycle progression. We analyzed the expression of proteasome subunits in anaplastic thyroid carcinoma and found that proteasome subunit C2 and proteasome activator g (PA28g) are highly expressed in its rapid-growing cancer cells. This result is repeatedly confirmed by western blotting and imm … More unocytochemistry, when other types of thyroid carcinoma were also estimated. Interestingly, PA 28g is localized in nuclei of cancer cells, suggesting PA28g could be one of the good candidate for manipulating the growth of cancer cells. We then analyzed the detailed turn-over of PA28g using rat functional thyroid cell line, FRTL5 cells. The growth-stimuli, TSH and insulin, induced PA28-γ expression in FRTL5 cell. Intere stingly, both treatment not only upregulate PA28-γ expression but also recruite PA28-γ from cytosol to nucleus. The combination of TSH and insulin showed highest inducibility of PA28-γ as well as dual DNA synthesis of FRTL5. Proteasome inhibitors such as lactacystin significantly blocked the DNA synthesis induced by TSH and insulin, indicating the intrinsic 20S proteasome is involved in thyroid cell growth. Thus, our results indicate PA28-γ is induced by goitrogenic factors, TSH and insulin, in thyroid cell and potentially contribute to thyroid cell growth by potentiating 20S proteasome activity.Taken together, overexpressed proteasome component such as C2 or PA28-γ will be good candidates for manipulating proteasome activity, thereby interfering with anaplastic cancer cell growth. Less

塑性甲状腺癌是老年人中发现的分化较差的癌。患有那种癌癌的患者的预后始终遭受不良的预后。制定有效策略来抑制变性癌的生长并延长患者预后是一项紧迫的业务。我们专注于ubiqitin-proteasome系统。蛋白酶体是一种主要的细胞内蛋白，作为大型蛋白质复合物，由至少14个不同但同源的亚基组成，分子质量为21-32 kD，它们被组装成大约700 kDa圆柱结构。它参与了负责生物学过程（例如细胞周期进程）的调节蛋白的破坏。我们分析了蛋白酶体亚基在甲状腺甲状腺癌中的表达，发现蛋白酶体亚基C2和蛋白酶体激活剂G（PA28G）在其快速生长的癌细胞中高度表达。当还估计了其他类型的甲状腺癌时，通过蛋白质印迹和IMM进行了反复确认此结果。有趣的是，PA 28G位于癌细胞的核细胞中，这表明PA28G可能是操纵癌细胞生长的好候选者之一。然后，我们使用大鼠功能性甲状腺细胞系FRTL5细胞分析了PA28G的详细转换。生长刺激，TSH和胰岛素在FRTL5细胞中诱导PA28-γ表达。垂直地，两者都在上调PA28-γ的表达，而且还从细胞质到核募集了PA28-γ。 TSH和胰岛素的组合表现出PA28-γ以及FRTL5的双DNA合成的高度诱导性。诸如乳囊蛋白之类的蛋白酶体抑制剂显着阻断了TSH和胰岛素诱导的DNA合成，表明固有的20S蛋白酶体与甲状腺细胞的生长有关。这是我们的结果表明，甲状腺细胞中的山羊皮因子TSH和胰岛素可以诱导PA28-γ，并有可能通过20S蛋白酶体活性导致甲状腺细胞的生长。综上所述，过表达的蛋白酶体成分（例如C2或PA28-γ）将是操纵蛋白酶体活性的良好候选者，从而干扰了变性癌细胞的生长。较少的

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Shin-ichi Taniguchi, Tomohisa Okamura, Yuka Santo, Hiroko Fukui, Hideki Shimizu, Akio Yoshida, Yoshihiko Ueta and Chiaki Shigemasa: "Proteasome activator 28-γ (PA28-γ) is induced by goitrogenic factors-TSH and insulin in thyroid cell"Journal of Clinical E

Shin-ichi Taniguchi、Tomohisa Okamura、Yuka Santo、Hiroko Fukui、Hideki Shimizu、Akio Yoshida、Yoshihiko Ueta 和 Chiaki Shigemasa：“蛋白酶体激活剂 28-γ (PA28-γ) 由甲状腺细胞中的致甲状腺肿因子 - TSH 和胰岛素诱导”临床电子杂志