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Identification of molecules regulating resistance and invasiveness of malignant gliomas and development of new therapeutic approaches

恶性神经胶质瘤耐药性和侵袭性调节分子的鉴定及新治疗方法的开发

基本信息

批准号：
17209049
负责人：
SAYA Hideyuki
金额：
$ 32.2万
依托单位：
KEIO UNIVERSITY (2006)Kumamoto University (2005)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

The prognosis of patients with malignant glioma is extremely poor, despite the development of new therapeutic approaches. This difficulty is considered to be due to the high invasiveness and drug-resistance characteristics of glioma cells. The objectives of the present project are to identify molecules regulating resistance and invasiveness of malignant gliomas and to develop new therapeutic approaches for the tumors. The major findings we obtained are as follows :1)Mitotic catastrophe is an important mechanism for the induction of cell death in cancer cells by antineoplastic agents. We tried to identify the critical signal pathways to regulate the paclitaxel-induced mitotic catastrophe. Among diverse intracellular kinases, p38 MAP kinase was significantly and specifically activated when cells underwent mitotic death.The activation of p38 requires the long-term metaphase arrest and is triggered as cell goes from metaphase to anaphase. Moreover, we found that the p38 activation is induced by the oxidative stress which is increased during metaphase arrest. Therefore, treatment with either anti-oxidants or p38 inhibitor suppressed the paclitaxel-induced mitotic catastrophe.Furthermore, we found that the drug resistance characteristics of U251MG glioma cells are based on the inactivation of p38 kinase pathway2)We found that turnover of interaction between CD44 adhesion molecule and hyaluronic acid is a crucial factor for glioma cell invasion in extracellular matrix. Especially, we show that HAS3-dependent synthesis of hyaluronic acid plays an important role in leading edge formation and that inhibition of HAS3 expression blocks the matrix invasion of glioma cells.

恶性胶质瘤患者的预后极差，尽管开发了新的治疗方法。这一困难被认为是由于胶质瘤细胞的高侵袭性和耐药性特征。本研究的目的是鉴定恶性胶质瘤耐药性和侵袭性的调控分子，并开发新的治疗方法。主要结果如下：1）有丝分裂灾难是化疗药物诱导癌细胞死亡的重要机制。我们试图找出调节紫杉醇诱导的有丝分裂灾难的关键信号通路。在众多的细胞内激酶中，p38MAP激酶在细胞发生有丝分裂死亡时被显著而特异地激活，p38的激活需要长期的中期停滞，并在细胞从中期进入后期时被触发。此外，我们发现，p38激活诱导的氧化应激，这是增加中期阻滞。此外，我们还发现U251 MG胶质瘤细胞的耐药特征是基于p38激酶通路的失活。2）我们发现CD44粘附分子和透明质酸之间相互作用的转换是胶质瘤细胞侵袭细胞外基质的关键因素。特别是，我们表明，HAS3依赖性的透明质酸合成在前沿形成中起着重要作用，HAS3表达的抑制阻断了胶质瘤细胞的基质侵袭。

项目成果

期刊论文数量（25）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mitogenic signaling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence.

有丝分裂信号传导和 p16INK4a-Rb 通路协同作用，强制细胞发生不可逆转的衰老。

DOI：
发表时间：
2006
期刊：
Nat Cell Biol 8
影响因子：
0
作者：
野杁由一郎;ら;Takahashi A. et al.
通讯作者：
Takahashi A. et al.

Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation

DOI：
10.1038/sj.onc.1210042
发表时间：
2007-04-12
期刊：
ONCOGENE
影响因子：
8
作者：
Kuninaka, S.;Iida, S-I;Saya, H.
通讯作者：
Saya, H.

Multiple roles of vertebrate REV genes in DNA repair and recombination

DOI：
10.1128/mcb.25.14.6103-6111.2005
发表时间：
2005-07-01
期刊：
MOLECULAR AND CELLULAR BIOLOGY
影响因子：
5.3
作者：
Okada, T;Sonoda, E;Takeda, S
通讯作者：
Takeda, S

Centrosome amplification in adult T‐cell leukemia and human T‐cell leukemia virus type 1 Tax‐induced human T cells

DOI：
10.1111/j.1349-7006.2006.00254.x
发表时间：
2006-09
期刊：
Cancer Science
影响因子：
5.7
作者：
Takayuki Nitta;M. Kanai;E. Sugihara;Masakazu Tanaka;Binlian Sun;T. Nagasawa;S. Sonoda;H. Saya;M. Miwa
通讯作者：
Takayuki Nitta;M. Kanai;E. Sugihara;Masakazu Tanaka;Binlian Sun;T. Nagasawa;S. Sonoda;H. Saya;M. Miwa

RNA interference targeting aurora kinase A suppresses tumor growth and enhances the taxane chemosensitivity in human pancreatic cancer cells