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Identification of novel genes that determine cell's sensitivity to anticancer treatments/cell death in malignant tumors of neuronal origin

确定神经元恶性肿瘤中细胞对抗癌治疗/细胞死亡的敏感性的新基因的鉴定

基本信息

批准号：
18390389
负责人：
KITANAKA Chifumi
金额：
$ 5.64万
依托单位：
Yamagata University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390389/
关键词：
Warburg effect mitochondria energy metabolism programmed cell death glycolysis グリオーマ Ras JNK

项目摘要

Cancer cells have a propensity to produce energy (=ATP) in an anaerobic manner even in the presence of ample oxygen, which is termed Warburg effect Warburg effect is thus a common phenotype of cancer cells and forms a basis for cancer detection by 18-fluorodeoxyglucose positron emission tomography ([^<18>F]FDG-PET) scans. However, why cancer cells choose to rely heavily on such an inefficient way of energy production (〜1/20 efficient compared to aerobic energy production) has remained a mystery for nearly 80 years since the discovery of Warburg effect In this research project, we have discovered that the aerobic energy metabolism, but not the anaerobic one, plays a pivotal role in the activation of Bax and Bak essential for mitochondria mediated cellular suicide (Tomiyama, et. Al., J Natl Cancer Inst 98: 1462-1473, 2006. This paper was selected as a "Research Highlight" in the December issue of Nature Reviews Cancer, 2006). Since cancer cells, unlike normal cells, are continuously exposed to various external and internal stimuli that cause them to commit suicide, cancer cells need to actively avoid suicide to survive and grow. Thus, with our discovery, the "seemingly absurd energy metabolism" of cancer cells can now be viewed as a "crafty strategy" to avoid suicide commitment at the cost of energy production efficiency.Another important implication of our findings in light of cancer therapeutics is that, if we can shift the metabolism of cancer cells from anaerobic to aerobic, then we can sensitize them to conventional cancer therapies, which often depend on the mitochondria mediated suicide mechanism for cell killing. In this respect, we have recently identified a natural compound that promotes aerobic metabolism of glioblastoma (GBM) cells. In the future project, we will be investigating whether this compound is useful in overcoming therapy resistance inherent to GBM cells.

癌细胞具有即使在充足的氧气存在下也以厌氧方式产生能量（=ATP）的倾向，这被称为瓦尔堡效应。因此，瓦尔堡效应是癌细胞的常见表型，并且形成通过18-氟脱氧葡萄糖正电子发射断层扫描（[<18>18F]FDG-PET）扫描进行癌症检测的基础。然而，为什么癌细胞选择严重依赖这种低效的能量生产方式呢？（与有氧能量产生相比效率为1/20）自从发现瓦尔堡效应以来，近80年来一直是个谜在这个研究项目中，我们发现有氧能量代谢，而不是无氧能量代谢，在线粒体介导的细胞自杀所必需的Bax和巴克的活化中起关键作用（Tomiyama，et.艾尔J Natl Cancer Inst 98：1462-1473，2006.该论文被《Nature Reviews Cancer》2006年12月刊选为“研究亮点”。由于癌细胞与正常细胞不同，会持续暴露于各种导致其自杀的外部和内部刺激，因此癌细胞需要主动避免自杀才能生存和生长。因此，随着我们的发现，癌细胞的“看似荒谬的能量代谢”现在可以被视为一种“狡猾的策略”，以避免以能量生产效率为代价的自杀行为。我们的发现在癌症治疗方面的另一个重要意义是，如果我们可以将癌细胞的代谢从厌氧转变为有氧，那么我们就可以使它们对传统的癌症治疗敏感，其通常依赖于线粒体介导的细胞杀伤自杀机制。在这方面，我们最近发现了一种天然化合物，可促进胶质母细胞瘤（GBM）细胞的有氧代谢。在未来的项目中，我们将研究这种化合物是否有助于克服GBM细胞固有的治疗抗性。