Ferroptosis, Cellular Metabolism, and Cancer

铁性下垂、细胞代谢与癌症 摘要 细胞程序性死亡在正常生物学中扮演着重要的角色，而细胞程序性死亡的解除对生物的影响是多种多样的 人类疾病，包括癌症。最近的进展表明，除了细胞凋亡，这是 除了最成熟的程序性细胞死亡模式外，还有其他形式的程序性细胞死亡。 铁性下垂是一种新出现的程序性坏死过程，它涉及多种生物学和 病理情况。然而，其确切的机制和功能还不是很清楚。 这项建议的总体目标是研究铁性下垂的分子基础及其潜在的可能性。 与癌症有关。这一建议是基于我们最近的发现，即铁性下垂的诱导需要 细胞外铁载体蛋白转铁蛋白和细胞内代谢过程谷氨酰胺分解；以及抑制 谷氨酰胺分解，可能是通过阻断铁下垂，减少由缺血-再灌注引发的心脏损伤。 因为转铁蛋白和谷氨酰胺分解对癌细胞的活力都是至关重要的，我们的发现是 参与诱导一种特定类型的细胞死亡在概念上是耐人寻味的和意想不到的。另外， 我们的初步研究表明，铁性下垂的执行需要活跃的线粒体功能，进一步 强调了铁下垂与细胞代谢和氧化还原机制之间的密切关系。 最后，我们鉴定了癌基因产物myc，它是细胞新陈代谢和线粒体的主要调节因子。 功能，作为铁性下垂的正向调节。 在这些初步结果的基础上，在这项建议中，我们将进一步研究铁性上睑下垂的分子基础 通过重点研究谷氨酰胺分解、铁信号和线粒体的作用和功能相互作用，在 下垂(AIMS-1和AIMS-2)。我们还将调查铁性上睑下垂与癌症的相关性。尤其是，由于许多人 癌细胞具有MYC的过度表达和高水平的谷氨酰胺分解，因此可能更容易受到影响 对于铁下垂，我们能否利用癌细胞的这种特性(阿喀琉斯之踵)来发展以铁下垂为基础的癌症 治疗？AIM-3中提出的实验有望为这一与癌症相关的问题提供见解。

Ferroptosis, Cellular Metabolism, and Cancer Summary Programmed cell death plays important roles in normal biology, and its deregulation impacts various human diseases, including cancer. Recent progress has established that in addition to apoptosis, which is the best-established mode of programmed cell death, there are also other forms of programmed cell death. Ferroptosis is a newly emerged programmed necrosis process that is implicated in multiple biological and pathological conditions. However, its precise mechanism and function are not well understood. The overall goal of this proposal is to investigate the molecular basis of ferroptosis and its potential involvement in cancer. This proposal is based on our recent finding that induction of ferroptosis requires the extracellular iron-carrier protein transferrin and the intracellular metabolic process glutaminolysis; and inhibition of glutaminolysis, presumably via blocking ferroptosis, reduces heart injury triggered by ischemia-reperfusion. Because both transferrin and glutaminolysis are crucial for cancer cell viability, our finding that they are involved in the induction of a specific type of cell death is conceptually intriguing and unexpected. Additionally, our preliminary studies indicate that execution of ferroptosis requires active mitochondrial function, further underscoring the intimate relationship between ferroptosis and cellular metabolic and redox machineries. Lastly, we identified the oncogene product MYC, a master regulator of cellular metabolism and mitochondrial function, as a positive regulator of ferroptosis. Based on these preliminary results, in this proposal, we will further study the molecular basis of ferroptosis by focusing on the role and functional interplay of glutaminolysis, iron signaling, and mitochondria, in ferroptosis (Aims-1 & 2). We will also investigate the cancer relevance of ferroptosis. Particularly, as many cancer cells possess MYC overexpression and high levels of glutaminolysis, thus likely to be more susceptible to ferroptosis, can we exploit this property of cancer cells (Achilles heel) to develop ferroptosis-based cancer therapies? Experiments proposed in Aim-3 are expected to provide insights into this cancer-relevant question.