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:
  • 金额:
    $ 3.9万
  • 依托单位:
  • 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

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

项目成果

期刊论文数量(0)
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Amy Elizabeth Stewart其他文献

Amy Elizabeth Stewart的其他文献

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{{ truncateString('Amy Elizabeth Stewart', 18)}}的其他基金

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
  • 批准号:
    10154758
  • 财政年份:
    2021
  • 资助金额:
    $ 3.9万
  • 项目类别:

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