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Defining the Mechanistic Determinants of Response to Selective Electron Transport Chain Inhibition in Cancer

定义癌症选择性电子传递链抑制反应的机制决定因素

基本信息

批准号：
10362553
负责人：
Amy Elizabeth Stewart
金额：
$ 3.9万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10362553
关键词：
Address Antidiabetic Drugs Antimycin A Biological CRISPR screen Cancer Model Cancer cell line Cell Culture Techniques Cell Death Cell Line Cell Survival Cell physiology Cells Cholesterol Clinic Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Combined Modality Therapy Complex Culture Media DHODH gene Data Dependence Diabetes Mellitus Dose Drug Targeting Electron Transport Electron Transport Complex III Energy Metabolism Enzymes Exhibits Generations Genes Glycolysis Heterogeneity Immune Immunocompetent In Vitro Incidence Individual Knock-out Knowledge Link Malignant Neoplasms Measures Metabolic Metabolic Pathway Metabolism Metformin NADH dehydrogenase (ubiquinone)Oxidation-Reduction Oxidative Phosphorylation Pathway interactions Patients Pharmaceutical Preparations Play Production Pyrimidine Reaction Regulation Role Series Testing Therapeutic Therapeutic Effect Treatment Efficacy Ubiquinone Warburg Effect Work base cancer cell cancer risk cancer therapy diabetic patient expectation experimental study in vivo inhibitor interest isoprenoid melanoma metabolomics mevalonate mouse model neoplastic cell novel response translational potential treatment response tumor initiation tumor progression

项目摘要

Abstract: Cells utilize two major modes of energy metabolism: glycolysis and oxidative phosphorylation (OXPHOS). Efforts to target metabolism in cancer have mainly focused on glycolysis due to the observation that cancer cells preferentially utilize this mode, termed the Warburg effect. However, there is renewed interest in targeting OXPHOS through its effector, the electron transport chain (ETC), primarily because of the discovery that the widely used anti-diabetic drug, metformin, lowers risk of cancer incidence in diabetes patients and kills cancer cells in vitro and in vivo through inhibiting complex I of the ETC. The ETC is composed of five complexes that work to sequentially transfer electrons in a series of redox reactions that result in the generation of ATP. As the efforts to target the ETC in cancer are relatively recent, fundamental knowledge such as the landscape of dependence on the ETC and more specifically, particular ETC complexes, across cancers remains unknown. To investigate these questions, our lab has defined the dependence on inhibition of each ETC complex across a large panel of diverse cancer cell lines. Intriguingly, cell lines respond variably to inhibition of individual ETC complexes, with complex I inhibition yielding homogeneous cell death and complex II-V inhibition causing heterogeneous cell death. We naively expected that ETC complex dependencies would correlate with each other due to the linearity of the ETC; additional preliminary data show that ATP levels remain unchanged with ETC inhibition. Taken together, these results suggest that ETC complexes may play important roles in maintaining cell viability independently of their canonical roles in OXPHOS. To that end, we performed CRISPR/Cas9 screens and metabolomics analyses to determine the non- canonical metabolic mechanisms modulating ETC complex dependences. We identified various biosynthetic metabolic pathways that modulate, and are modulated by, individual ETC complex inhibition. Of particular interest, we identified a novel synthetic lethal combination between complex III inhibition and loss of the mevalonate pathway that has promising translational potential. The mevalonate pathway synthesizes various isoprenoids, such as cholesterol and ubiquinone, and has been implicated in tumor initiation and progression; additionally, this pathway is inhibited by statin drugs, commonly used in the clinic to lower cholesterol levels. As mechanisms describing the regulation of complex III by the mevalonate pathway have not yet been elucidated, this is an interesting relationship to investigate for both basic and translational reasons. In this proposal, we will investigate the hypothesis that ubiquinone synthesis regulates the relationship between the mevalonate pathway and complex III. We will also determine if the efficacy of complex III inhibition can be enhanced by using statins in both immune-competent and immune-deficient mouse models of cancer.

细胞利用两种主要的能量代谢模式：糖酵解和氧化磷酸化