Identification of molecules regulating resistance and invasiveness of malignant gliomas and development of new therapeutic approaches
| Project/Area Number |
17209049
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Cerebral neurosurgery
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| Research Institution | KEIO UNIVERSITY (2006)
Kumamoto University (2005) |
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Principal Investigator |
SAYA Hideyuki Keio University, School of Medicine, Professor, 医学部, 教授 (80264282)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥50,310,000 (Direct Cost: ¥38,700,000、Indirect Cost: ¥11,610,000)
Fiscal Year 2006: ¥24,050,000 (Direct Cost: ¥18,500,000、Indirect Cost: ¥5,550,000)
Fiscal Year 2005: ¥26,260,000 (Direct Cost: ¥20,200,000、Indirect Cost: ¥6,060,000)
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| Keywords | Cancer / Gene / Cell / Brain / Mitosis / Adhesion molecule / Drug resistance / Invasion / 脳腫瘍 / グリオーマ / 抗がん剤 / 細胞周期 / 細胞死 / 酸化ストレス / CD44 / ヒアルロン酸 |
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| Research Abstract |
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 pathway
2)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.
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Report
(3 results)
Research Products
(26 results)
