Vaccination therapy against malignant glioma using apoptosis-inducing genes

使用细胞凋亡诱导基因针对恶性神经胶质瘤的疫苗治疗

• 批准号: 07407038
• 负责人: ASAI Akio
• 金额: $ 23.23万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07407038/
• 关键词: Apoptosis; glioma; calcineurin; proteasome; ワクチン療法; differential display PCR

We cloned several genes whose expression level increase or decrease along with the progression of myc-induced apoptosis in glioma cells by differential display PCR method. One of the genes was calmodulin. Therefore, in this study, we hypothesized that calciummediated signal transduction may be involved in apoptosis and the activation of immunogenicity in malignant glioma cells and tried to investigate their molecular mechanism by confirming the hypothesis. Although we have not reached the final goal, we have found the following several important findingsregarding molecular mechanisms of apoptosis : (1) the expression level of calcineurin is extremely high in the brain as was reported ; (2)when the activity of calcineurin increases, the activity of proteasome decreases ; (3)when the proteasome activity was perturbed by inhibitors, apoptosis is induced in the cells ; (4)as a result, the cells with high calcineurin activity are vulnerable to apoptosis. These results may elucidate that hippocampal CA1 neurons with high calcineurin expression are vulnerable to delayd neuronal death induced by transient iscemia although these results are not exclusive to neural cells. It is probable that gliomaspecific mechanisms such as sctivation of tumor-immunogenicity are located downstream of the proteasome function. It is extremely important to clarify the function of proteasome in apoptosis and activation of tumor-immunogenicity and such a project is in progress.

我们克隆了几个基因，这些基因通过差异显示PCR方法，其表达水平随着MYC诱导的细胞中胶质瘤细胞凋亡的进展而增加或降低。其中一个基因是钙调蛋白。因此，在这项研究中，我们假设钙介导的信号转导可能与恶性神经胶质瘤细胞中的凋亡有关和免疫原性的激活，并试图通过确认假设来研究其分子机制。尽管我们尚未达到最终目标，但我们发现了凋亡的分子机制以下几个重要发现：（1）钙调蛋白的表达水平在大脑中非常高； （2）当钙调蛋白的活性增加时，蛋白酶体的活性会降低； （3）当蛋白酶体活性受到抑制剂的干扰时，细胞中诱导凋亡； （4）因此，具有钙调蛋白磷酸酶活性的细胞容易受到细胞凋亡的影响。这些结果可能会阐明具有高钙调蛋白表达的海马CA1神经元很容易受到瞬时ISCEMIA诱导的延迟神经元死亡的影响，尽管这些结果并不是神经细胞独有的。诸如肿瘤免疫原性的静脉成分之类的神经胶质性机制可能位于蛋白酶体功能的下游。阐明蛋白酶体在凋亡中的功能和肿瘤免疫原性的激活以及这种项目正在进行中非常重要。

项目成果

Asai A, et al.: "Abundant expression of translation initiation factor EIF-4E in post-meiotic germ cells of the rat testis." Lab Invest. 72. 890-898 (1995)

Asai A 等人：“翻译起始因子 EIF-4E 在大鼠睾丸减数分裂后生殖细胞中大量表达。”

浅井昭雄: "グリオーマ細胞におけるアポトーシスと免疫原性変化の誘導" 脳神経外科. 23. 7-15 (1995)

Akio Asai：“神经胶质瘤细胞凋亡和免疫原性变化的诱导”《神经外科》23. 7-15 (1995)。

Asai A, et al.: "Caspase-dependent apoptosis of COS-7 cells induced by Bax overexpression:differential effects of Bcl-2 and Bcl-xL on Bax-induced caspase activation" Oncogene. 15. 1471-1480 (1997)

Asai A 等人：“Bax 过表达诱导的 COS-7 细胞的 Caspase 依赖性凋亡：Bcl-2 和 Bcl-xL 对 Bax 诱导的 caspase 激活的差异作用”Oncogene。

Asai A,et al.: "s-Myc acts as a transcriptional activator and its sequence-specific DNA binding is required for induction of programd cell death in glioma cells." Cell Death Differ. 2. 123-131 (1995)

Asai A 等人：“s-Myc 充当转录激活剂，其序列特异性 DNA 结合是诱导神经胶质瘤细胞程序性细胞死亡所必需的。”

Asai A, et al.: "Pim-kinase stimulates c-Myc-mediated death signaling upstream of capase-3 (CPP32)-like protease activation." Oncogene. 15. 1471-1480 (1997)

Asai A 等人：“Pim 激酶刺激 c-Myc 介导的 capase-3 (CPP32) 样蛋白酶激活上游的死亡信号传导。”