The Development of novel anticancer drugs for anaplastic thyroid carcinoma by collaboration of medicine and engineering

医工合作开发治疗甲状腺未分化癌的新型抗癌药物

• 批准号: 15590978
• 负责人: TANIGUCHI Shin-ichi
• 金额: $ 2.24万
• 依托单位: National University Corporation 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: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590978/
• 关键词: UBIQUITIN; PROTEASOME; ANAPLASTIC CARCINOMA; THYROID; WD REPEAT PROTEIN 1; 癌

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 ubiquitin-proteasome sytem. 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 21-32kD and they are assembled into an approximately 700kDa cylindcal structure. 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. Interestinglly, PA28g is localized in nuclei of cancer cells, suggesting PA28g, could be one of the good candidate for manipulating the growth of cancer cells. Proteasome inhibitors such as la … More ctacystin significantly blocked the DNA synthesis of thyroid carcinoma cell line, indicating the intrinsic 20S proteasome is involved in cancer cell growth. We then analyzed the detailed turn-over of PA28g using rat functional thyroid cell line, FRTL5 cells. Interestingly, TSH and insulin 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. 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.Simultaneously, we searched novel candidate genes for mapipulating the growth rate of anaplastic thyroid cancer. In order to isolate a novel gene, we used a unique strategy named SEREX. We used expression library derived from cancer tissue and surveyed 1X106 plaque by autologous patient sera. After all, we could isolate two positive clones. One of them was WD repeat protein 1(WDR1), which is the human counterpart of actin interacting protein 1. WDR1 is highly expressed in anaplastic thyroid cancer tissues, indicating that WDR1 could be involved in cancer cell proliferation. It still remains unclear that WDR1 protein is degraded by ubiquitin-proteasome dependent pathway. But, if it is degraded via proteasome-dependent fashion, WDR1 will be a good candidate for anti-cancer therapy. 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。我们专注于泛素蛋白酶体系统。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21-32KD，并且组装成大约700kDa圆柱结构。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。有趣的是，PA28G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良好候选者之一。蛋白酶体抑制剂，例如LA…更多的ctacystin显着阻断了甲状腺癌细胞系的DNA合成，表明固有的20S蛋白酶体参与癌细胞生长。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。有趣的是，TSH和胰岛素治疗不仅上调了PA28-γ的表达，而且还募集了从胞质溶胶到核us的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。这是我们的结果表明，甲状腺细胞中的山羊皮因子TSH和胰岛素诱导PA28-γ，并通过潜在的20S蛋白酶体活性来促进甲状腺细胞的生长。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。相似地，我们搜索了新的候选基因，用于对抗肿瘤性甲状腺甲状腺癌的生长速率进行绘制。为了隔离一个新型基因，我们使用了一个名为Serex的独特策略。我们使用了源自癌组织的表达文库，并通过自体患者血清调查了1x106斑块。毕竟，我们可以隔离两个阳性克隆。其中之一是WD重复蛋白1（WDR1），它是肌动蛋白相互作用蛋白1。WDR1在甲状腺甲状腺癌组织中高度表达的，这表明WDR1可能与癌细胞增殖有关。尚不清楚WDR1蛋白会因泛素 - 蛋白酶体依赖性途径而降解。但是，如果通过蛋白酶体依赖性时尚降解，WDR1将是抗癌治疗的良好候选者。较少的

项目成果

New perspectives in cancer research and therapy

癌症研究和治疗的新视角

• 发表时间: 2005
• 作者: Taniguchi S-I;Ohkura T;Okamura T;Santo Y;Fukui H;Yoshida A;Ueta Y;Shigemasa C;Shin-ichi Taniguchi
• 通讯作者: Shin-ichi Taniguchi

Detection of the novel autoantibody (anti-UACA antibody) in patients with Graves' disease.

• DOI: 10.1016/j.bbrc.2004.06.162
• 发表时间: 2004-08
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: T. Ohkura;Shin‐ichi Taniguchi;Kazuhiro Yamada;N. Nishio;T. Okamura;Akio Yoshida;Keiichi Kamijou;S. Fukata;K. Kuma;Y. Inoue;I. Hisatome;S. Senju;Y. Nishimura;C. Shigemasa

State-dependent blocking actions of azimilide dihydrochrolide (NE-10064) on human cardiac Na+ channel.

阿齐利特二氢氯化物 (NE-10064) 对人心脏 Na 通道的状态依赖性阻断作用。

• 发表时间: 2004
• 期刊: Circ J. 68・7
• 作者: Shin-ichi Taniguchi;Miake J
• 通讯作者: Miake J

Tomohisa Okamura: "Abnormally high expression of proteasome activator-γ in thyroid neoplasm"The Journal of Clinical Endocrinology & Metabolism. 88. 1374-1383 (2003)

Tomohisa Okamura：“甲状腺肿瘤中蛋白酶体激活剂-γ 的异常高表达”临床内分泌与代谢杂志 88. 1374-1383 (2003)。

Acute secondary gastrointestinal amyloidosis in a patient With rheumatoid arthritis.

类风湿性关节炎患者的急性继发性胃肠道淀粉样变性。

• 发表时间: 2003
• 期刊: Am J Med Sci 326・3
• 作者: Miake J;Kurata Y;Iizuka K;Furuichi H;Manabe K;Sasaki N;Yamamoto Y;Hoshikawa Y;Taniguchi S;Yoshida A;Igawa O;Makita N;Shiota G;Nanba E;Ohgi S;Narahashi T;Hisatome I.;Shimoyama M
• 通讯作者: Shimoyama M