程序性坏死诱导剂紫草素对脑胶质瘤的治疗作用及机制研究

Glioma is the most common intracranial malignant tumor with higher recurrence and mortality, but current treatment could not extend the life time of the patients with higher grade gliomas. The finding of necroptosis inducer shines a light on developing new treatment strategy and theory of gliomas. Our prior study showed that necroptosis inducer shikonin kills significantly C6 glioma cells in vitro and in vivo, and the inv vitro results showed that the effect is associated closely with higher expression of RIP-1, which is thought to play a pivotal role in mediating necroptosis. However, it is still unclear the mechanism underlying the activation of RIP-1 and its subsequent biological effects. In this project, we will investigate the mechanism underlying RIP-1 activation in gliomas and the role of ERK and JNK pathways in necroptosis, by using glioma cell lines in vitro and transplanted glioma cells in vivo. We hope that, via this study, it could be clarified the mechanism underlying glioma necroptosis and the effects of necroptosis induction in glioma treatment.

脑胶质瘤是颅内最常见的具有高复发率和高死亡率特点的恶性肿瘤，目前的治疗方法均不能显著延长高级别（III-IV级）脑胶质瘤患者的生存期。程序性坏死诱导剂的发现为探讨脑胶质瘤的治疗理论和策略提供了一个新的思路。我们前期研究发现程序性坏死诱导剂紫草素显著抑制了大鼠脑内C6胶质瘤细胞的生长，体外研究显示紫草素激活了胶质瘤细胞内由受体相互作用蛋白激酶1（RIP-1）介导的程序性坏死通路。但是，在紫草素的作用下，胶质瘤细胞内调节RIP-1表达的上游信号分子、RIP-1表达后的激活机制以及激活后的下游信号途径等问题尚不清楚。因此，在本课题中，我们拟采用体外培养的胶质瘤细胞系以及接种到裸鼠皮下和大鼠脑内的胶质瘤细胞为研究对象，采用RNA干扰、免疫沉降、蛋白印迹分析等方法对以上问题进行探讨。我们期望通过该研究，明确脑胶质瘤细胞中程序性坏死发生的机制以及诱导程序性坏死在脑胶质瘤治疗中的作用。