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Methionine Dependency of Cancer

癌症的蛋氨酸依赖性

基本信息

批准号：
10016225
负责人：
Peter Kaiser
金额：
$ 16.8万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-11 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10016225
关键词：
Affect Animal Model Animals Apoptosis Behavior Betaine Binding Biological Biological Markers CRISPR/Cas technology Cancer Cell Growth Carbon Cell Cycle Arrest Cell Proliferation Cell Survival Cells Choline Chromatin Clinic Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Coin Combined Modality Therapy Complex Culture Media Cysteine Data Defect Dependence Diet Dietary Intervention Drops Essential Amino Acids Folic Acid Glutathione Disulfide Growth Homeostasis Homocysteine Human Individual Isoleucine Knock-out Libraries Link Malignant Neoplasms Mass Spectrum Analysis Mediating Mediator of activation protein Membrane Metabolic Metabolic Pathway Metabolism Methionine Methionine Metabolism Pathway Methylation Modality Molecular Normal Cell Pathway interactions Patients Pharmaceutical Preparations Phase Phospholipids Phosphoric Monoester Hydrolases Plasma Positron-Emission Tomography Proliferating Protein Phosphatase 2A Regulatory Subunit PR53 RNA RNA Caps Rattus Reducing diet Reporting S-Adenosylhomocysteine S-Adenosylmethionine Series Serum Solid Neoplasm Stress Supplementation Therapeutic Thiones Tissues Translations Valine base cancer cell cancer therapy dietary restriction experimental study genome-wide kinase inhibitor leukemia metabolomics methionylmethionine potential biomarker response screening small molecule tumor tumor growth

项目摘要

Project Summary Over 30 years ago it was discovered that cancer cells show a unique metabolic requirement for methionine that separates them from normal cells. This phenomenon is called “methionine dependence of cancer” or “methionine sensitivity of cancer” and describes the growth behavior of cancer cells when methionine is replaced with its immediate metabolic precursor homocysteine. While non-tumorigenic cells proliferate at normal rates in homocysteine medium, the overwhelming majority of cancer cells induces cell cycle arrest followed by apoptosis when cultured in homocysteine conditions. While conversion of homocysteine to methionine is not defective in cancer cells, these growth conditions appear to reduce the flux through the one-carbon cycle, which seems to primarily affect cancer cell growth. The dependence on high metabolic flux through methionine metabolism is also observed in solid tumors and leukemias. While the phenomenon of methionine sensitivity of cancer promises great therapeutic potential, it has been difficult to sufficiently reduce methionine availability in patients to trigger tumor regression through dietary restrictions alone. It is thus essential to understand the underlying mechanisms that govern methionine dependence of cancer. We therefore respond to the NCI’s provocative question 11 (Through what mechanisms do diet and nutritional interventions affect the response to cancer treatment?) and aim to understand molecular mechanisms that trigger methionine sensitivity of cancer, and discover treatment modalities that are enhanced by reduced methionine availability.

项目摘要 30多年前，人们发现癌细胞显示出独特的代谢需求，甲硫氨酸将它们与正常细胞分开。这种现象被称为“甲硫氨酸癌症的甲硫氨酸依赖性”或“癌症的甲硫氨酸敏感性”，并描述了当蛋氨酸被其直接代谢前体同型半胱氨酸取代时，癌细胞中的蛋氨酸会发生变化。而非致瘤细胞在同型半胱氨酸培养基中以正常速率增殖，绝大多数当在同型半胱氨酸中培养时，条件虽然高半胱氨酸向甲硫氨酸的转化在癌细胞中没有缺陷，但这些缺陷在癌细胞中并不存在。生长条件似乎减少了通过一碳循环的通量，这似乎主要是影响癌细胞生长。通过甲硫氨酸代谢对高代谢通量的依赖是也在实体瘤和白血病中观察到。而甲硫氨酸敏感现象癌症有巨大的治疗潜力，但很难充分减少蛋氨酸在患者中，仅通过饮食限制就可以触发肿瘤消退。因此，了解控制癌症的蛋氨酸依赖性的潜在机制。我们因此，对NCI的挑衅性问题11（通过什么机制饮食和营养干预影响对癌症治疗的反应？）并致力于了解分子触发癌症的甲硫氨酸敏感性的机制，并发现通过降低蛋氨酸的可用性而增强。