Molecular basis for the induction of vaults by anti-cancer agents, and the role of vaults in resistance to anti-cancer agents.

抗癌剂诱导穹窿的分子基础，以及穹窿在抗癌剂抵抗中的作用。

• 批准号: 21590168
• 负责人: YAMADA Katsushi
• 金额: $ 2.75万
• 依托单位: Kagoshima University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21590168/
• 关键词: Vaults; 抗がん剤耐性; apoptosis; caspase; adriamycin; major vault protein; Sp-1; vault; caspase 3; E-box; upstream stimulatory factor 1

The major vault protein(MVP) is the main constituent of the vault ribonucleoprotein particle. Although the role in multidrug resistance has been suggested, the physiological function of vaults remains unclear. It has been reported that MVP levels were elevated after treatment with the DNA-damaging agents such as adriamycin(ADR). The aim of this study was to investigate molecular basis for the induction of MVP by ADM, and to investigate the potential role of MVP in drug resistance. Expression levels of both MVP protein and MVP mRNA were increased by ADM. ADM could also enhance MVP promoter activity. Introduction of siRNA against Sp-1 in SW620cells attenuated the expression of MVP induced by ADM. Down-regulation of MVP expression by MVP RNAi in SW620cells increased the sensitivity of the cells to ADM. Furthermore, ADM enhanced the activation of caspase 3 and caspase 8 in the MVP knock-down cells, but not in control cells. Our data demonstrate that exposure of cancer cells to DNA-damaging agents induces MVP that might have an important role in the resistance to chemotherapeutic agents.

主要的拱顶蛋白(MVP)是拱顶核糖核蛋白颗粒的主要组成部分。虽然已经提出在多药耐药中的作用，但拱顶的生理功能仍不清楚。有报道称，经阿霉素(ADR)等DNA损伤剂治疗后，MVP水平升高。本研究的目的是探讨ADM诱导MVP的分子基础，以及MVP在耐药中的潜在作用。ADM可上调MVP蛋白和MVP mRNA的表达水平。ADM还能增强MVP启动子的活性。在SW620细胞中引入针对Sp-1的siRNA可减弱ADM诱导的MVP的表达。MVP RNAi下调SW620细胞MVP表达，增加细胞对ADM的敏感性。此外，ADM可增强MVP基因敲除细胞中caspase3和caspase8的活性，但对对照细胞无明显影响。我们的数据表明，癌细胞暴露在DNA损伤剂中会诱导MVP，这可能在化疗药物的耐药性中发挥重要作用。

项目成果

Isolation and Characterization of Erlotinib-resistant in Human Non-small Cell Lung Cancer A549cells

人非小细胞肺癌 A549 细胞中厄洛替尼耐药的分离和表征

• 发表时间: 2011
• 期刊: Oncology Letters
• 影响因子: 2.9
• 作者: Ikeda;R.;Vermeulen;L. C.;Lau;E.;Jiang;Z.;Kavanaugh;S. M.;Yamada;K.;Kolesar;J. M.
• 通讯作者: J. M.

Gemcitabine and Paclitaxel Repress the Production of Vascular Endothelial Growth Factor Induced by Deferoxamine in Human Non-small Cell Lung Cancer A549cells

吉西他滨和紫杉醇抑制去铁胺诱导的人非小细胞肺癌A549细胞中血管内皮生长因子的产生

• 发表时间: 2010
• 期刊: Experimental and Therapeutic Medicine
• 影响因子: 2.7
• 作者: Ikeda;R.;Vermeulen;L. C.;Jiang;Z.;Lau;E. and Kolesar;J. M.
• 通讯作者: J. M.

チミジンホスホリラーゼ発現腫瘍での5-fluorouracil (5-FU)によるearly gr owth response factor-1 (EGR-1)発現誘導

5-氟尿嘧啶 (5-FU) 在胸苷磷酸化酶表达肿瘤中诱导早期生长反应因子 1 (EGR-1) 表达

• 发表时间: 2009
• 作者: 西澤由紀彦;池田龍二;田實裕介;俣木博徳;武田泰生;古川龍彦;牛山美奈;山口辰哉;車暁芳;山本雅達;松下茂人;秋山伸一;山田勝士
• 通讯作者: 山田勝士

Effect of 5-Fluorouracil Treatment on SN-38 Absorption from Intestine in Rats

• DOI: 10.1248/bpb.34.1418
• 发表时间: 2011-09-01
• 期刊: BIOLOGICAL & PHARMACEUTICAL BULLETIN
• 影响因子: 2
• 作者: Shibayam, Yoshihiko;Iwashita, Yoshitaka;Iseki, Ken
• 通讯作者: Iseki, Ken

抗がん剤耐性機序の解明に向けて

阐明抗癌药物耐药机制

• 发表时间: 2011
• 作者: Fujita K;Sugiura T;Okumura H;Umeda S;Nakamichi N;Sasaki Y;Kato Y;元木啓介;池田龍二,武田泰生,山田勝士
• 通讯作者: 池田龍二,武田泰生,山田勝士