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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Perturbational profiling of a cell-line model of tumorigenesis by using metabolic measurements
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Perturbational profiling of a cell-line model of tumorigenesis by using metabolic measurements

机译：通过代谢测量对肿瘤发生的细胞系模型进行微扰分析

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Weinberg and coworkers have used serial transduction of a human, primary fibroblast cell line with the catalytic domain of human telomerase, large T antigen, small T antigen, and an oncogenic allele of H-ras to study stages leading toward a fully transformed cancerous state. We performed a three-dimensional screening experiment using 4 cell lines, 5 small-molecule pertur-bagens (2-deoxyglucose, oxamate, oligomycin, rapamycin, and wortmannin), and a large number of metabolic measurements. Hierarchical clustering was performed to obtain signatures of the 4 cell lines, 24 cell states, 5 perturbagens, and a number of metabolic parameters. Analysis of these signatures and sensitivities of the cell lines to the perturbagens provided insights into the bioenergetic states of progressively transformed cell lines, the effect of oncogenes on small-molecule sensitivity, and global physiological responses to modulators of aerobic and anaerobic metabolism. We have gained insight into the relationship between two models of carcinogenesis, one (the Warburg hypothesis) based on increased energy production by glycolysis in cancer cells in response to aberrant respiration, and one based on cancer-causing genes. Rather than being opposing models, the approach described here suggests that these two models are interlinked. The cancer-causing genes used in this study appear to increase progressively the cell's dependence on glycolytic energy production and to decrease its dependence on mitochondria) energy production. However, mitochondrial biogenesis appears to have a more complex dependence, increasing to its greatest extent at an intermediate degree of transduction rather than at the fully transformed state.
机译：温伯格和同事已经使用人类端粒酶，大T抗原，小T抗​​原和H-ras致癌等位基因的催化结构域对人原代成纤维细胞系进行系列转导研究，研究了导致完全转化为癌态的阶段。我们使用4个细胞系，5个小分子pertur-bagens（2-脱氧葡萄糖，草酸盐，寡霉素，雷帕霉素和渥曼青霉素）进行了三维筛选实验，并进行了大量代谢测量。进行分层聚类以获得4个细胞系，24个细胞状态，5个扰动蛋白和许多代谢参数的特征。对细胞系对微扰的这些标记和敏感性的分析提供了对逐步转化的细胞系的生物能状态，癌基因对小分子敏感性的影响以及对需氧和厌氧代谢调节剂的整体生理反应的见解。我们已经了解了两种致癌模型之间的关系，一种模型（Warburg假设）基于糖酵解响应异常呼吸而增加的癌细胞能量产生，另一种模型基于致癌基因。这里描述的方法不是对立的模型，而是建议这两个模型是相互联系的。这项研究中使用的致癌基因似乎逐渐增加了细胞对糖酵解能量产生的依赖性，并降低了其对线粒体能量产生的依赖性。但是，线粒体的生物发生似乎具有更复杂的依赖性，在中等程度的转导而不是在完全转化的状态下最大程度地增加了它的依赖性。

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