Ferroptosis, Cellular Metabolism, and Cancer

铁死亡、细胞代谢和癌症

• 批准号: 9246212
• 负责人: Xuejun Jiang
• 金额: $ 39.27万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9246212
• 关键词: Aconitate Hydratase; Apoptosis; Biogenesis; Biological; Biology; Carrier Proteins; Cell Culture Techniques; Cell Death; Cell Survival; Cellular Metabolic Process; Development; Electron Transport; Enzymes; Event; GLS2 gene; Generations; Glutamine; Goals; Heart Injuries; Human; Hyperactive behavior; Iron; Iron Regulatory Protein 1; Ischemia; Isotopes; Light; Lipid Peroxidation; Lipid Peroxides; Malignant Neoplasms; Membrane Potentials; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Molecular; Mus; Necrosis; Oncogenic; Oncoproteins; Organelles; Oxidation-Reduction; Oxidative Phosphorylation; Pathologic; Pharmacology; Play; Process; Production; Property; Protein p53; Proteins; Reactive Oxygen Species; Regulation; Reperfusion Therapy; Reporting; Role; Signal Transduction; Stress; Testing; Transferrin; Xenograft Model; base; cancer cell; cancer therapy; cancer type; cell type; experimental study; extracellular; human disease; in vivo; insight; live cell imaging; metabolomics; mitochondrial membrane; novel; novel strategies; overexpression; treatment strategy

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.

铁凋亡、细胞代谢和癌症 总结 程序性细胞死亡在正常生物学中起着重要作用，其失调影响各种 人类疾病，包括癌症。最近的进展已经确定，除了细胞凋亡之外， 虽然程序性细胞死亡是最好的程序性细胞死亡模式，但也存在其他形式的程序性细胞死亡。 亚铁凋亡是一种新出现的程序性坏死过程，涉及多种生物学和病理学因素， 病理条件。然而，其确切的机制和功能还不清楚。 本提案的总体目标是研究铁凋亡的分子基础及其潜力 与癌症的关系这一建议是基于我们最近的发现，即铁凋亡的诱导需要 细胞外铁载体蛋白转铁蛋白和细胞内代谢过程的氨解;和抑制 可能通过阻断铁凋亡，减少缺血再灌注引起的心脏损伤。 因为转铁蛋白和β-氨基糖苷酶对癌细胞的生存能力都是至关重要的，我们发现它们是 参与诱导特定类型的细胞死亡在概念上是有趣的和出乎意料的。此外，本发明还 我们的初步研究表明，铁凋亡的发生需要活跃的线粒体功能， 强调了铁凋亡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，它是细胞代谢和线粒体的主要调节因子。 功能，作为一个积极的调节器的ferroptosis。 基于这些初步结果，在本提案中，我们将进一步研究铁凋亡的分子基础 通过关注多巴胺分解、铁信号传导和线粒体的作用和功能相互作用， 铁性下垂（目的1和2）。我们还将研究铁下垂与癌症的相关性。特别是，许多 癌细胞具有MYC过表达和高水平的精氨酸分解，因此可能更容易受到MYC的影响。 我们能否利用癌细胞的这种特性（致命弱点）来发展基于铁凋亡的癌症？ 治疗？Aim-3中提出的实验有望为这一癌症相关问题提供见解。