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

尽管开发了新的治疗方法，但恶性胶质瘤患者的预后非常差。这一困难被认为是由于胶质瘤细胞的高侵袭性和耐药特性造成的。本项目的目标是确定调节恶性胶质瘤耐药和侵袭性的分子，并开发新的肿瘤治疗方法。主要研究结果如下：1)有丝分裂突变是抗肿瘤药物诱导癌细胞死亡的重要机制。我们试图找出调控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，p38MAPK在细胞有丝分裂死亡时被显著和特异地激活，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，我们还发现，p38的激活是由中期停滞过程中增加的氧化应激诱导的。因此，抗氧化剂或p38抑制剂均可抑制紫杉醇诱导的有丝分裂灾难。此外，我们发现U251 MG胶质瘤细胞的耐药特性是基于p38激酶通路的失活。2)我们发现CD44黏附分子与透明质酸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，我们发现HAS3依赖的透明质酸合成在前沿的形成中起着重要作用，抑制HAS3的表达可以阻止胶质瘤细胞的基质侵袭。

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.