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

癌细胞即使在充足的氧气中也有以厌氧方式产生能量(=ATP)的倾向，这被称为Warburg效应Warburg效应因此是癌细胞的一种常见表型，并形成了通过18-氟脱氧葡萄糖正电子发射断层扫描(18&gt；18&gt；F]FDG-PET)检测癌症的基础。然而，为什么癌细胞选择严重依赖如此低效的能量产生方式(与有氧能量产生相比效率约1/20)一直是个谜近80年自Warburg效应被发现以来，我们发现有氧能量代谢，而不是无氧能量代谢，在激活Bax和Bak对于线粒体介导的细胞自杀至关重要(Tomiyama，et.等，美国国家癌症研究所98：1462-1473,2006。这篇论文被选为2006年12月出版的《自然·癌症评论》中的一篇《研究亮点》。由于癌细胞与正常细胞不同，不断暴露在各种外部和内部刺激下，导致它们自杀，因此癌细胞需要积极避免自杀才能生存和生长。因此，有了我们的发现，癌细胞的“看似荒谬的能量代谢”现在可以被视为一种以牺牲能源生产效率为代价来避免自杀承诺的“狡猾策略”。我们的发现在癌症治疗学中的另一个重要意义是，如果我们能够将癌细胞的新陈代谢从无氧转变为有氧，那么我们就可以使它们对传统的癌症疗法敏感，这通常依赖于线粒体介导的自杀机制来杀死细胞。在这方面，我们最近发现了一种天然化合物，可以促进胶质母细胞瘤(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细胞固有的治疗耐药性。

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.