Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides.
Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides.
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癌细胞对葡萄糖限制和双胍类药物敏感性的代谢决定因素。
DOI：
10.1038/nature13110
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发表时间：
2014-04-03
期刊：
影响因子：
64.8
通讯作者：
Sabatini, David M.
中科院分区：
文献类型：
--
作者：
Birsoy, Kivanc;Possemato, Richard;Lorbeer, Franziska K.;Bayraktar, Erol C.;Thiru, Prathapan;Yucel, Burcu;Wang, Tim;Chen, Walter W.;Clish, Clary B.;Sabatini, David M.
由于高度消耗的营养物质，特别是葡萄糖，在肿瘤中的浓度通常低于正常组织，癌细胞必须使其代谢适应肿瘤微环境。更好地理解这些适应可能会揭示癌细胞的负债，可以利用治疗的好处。在这里，我们开发了一种连续流动培养装置（Nutrostat），用于在低营养培养基中长时间维持增殖细胞，并使用它对在低葡萄糖条件下培养的条形码化癌细胞系的合并集合进行竞争性增殖测定。对低葡萄糖的敏感性在细胞系之间变化，并且RNAi筛选确定线粒体氧化磷酸化（OXPHOS）为在低葡萄糖中最佳增殖所需的主要途径。我们发现，对低葡萄糖最敏感的细胞系在OXPHOS上调方面存在缺陷，通常是由于复合体I基因中的线粒体DNA突变或葡萄糖利用受损而导致的葡萄糖限制引起的。当癌细胞在低葡萄糖中生长或作为肿瘤异种移植物生长时，这些缺陷预测了对双胍类、抑制OXPHOS的抗糖尿病药物的敏感性。值得注意的是，线粒体DNA突变的癌细胞的双胍敏感性被酵母NDI1的异位表达逆转，NDI1是一种泛醌氧化还原酶，允许绕过复合物I功能。因此，我们得出结论，线粒体DNA突变和受损的葡萄糖利用是潜在的生物标志物，用于识别肿瘤与增加敏感性OXPHOS抑制剂。
As the concentrations of highly consumed nutrients, particularly glucose, are generally lower in tumours than in normal tissues, cancer cells must adapt their metabolism to the tumour microenvironment. A better understanding of these adaptations might reveal cancer cell liabilities that can be exploited for therapeutic benefit. Here, we developed a continuous flow culture apparatus (Nutrostat) for maintaining proliferating cells in low nutrient media for long periods of time and used it to undertake competitive proliferation assays on a pooled collection of barcoded cancer cell lines cultured in low glucose conditions. Sensitivity to low glucose varies amongst cell lines, and an RNAi screen pinpointed mitochondrial oxidative phosphorylation (OXPHOS) as the major pathway required for optimal proliferation in low glucose. We found that cell lines most sensitive to low glucose are defective in the upregulation of OXPHOS normally caused by glucose limitation as a result of either mtDNA mutations in Complex I genes or impaired glucose utilization. These defects predict sensitivity to biguanides, anti-diabetic drugs that inhibit OXPHOS, when cancer cells are grown in low glucose or as tumour xenografts. Remarkably, the biguanide sensitivity of cancer cells with mtDNA mutations was reversed by ectopic expression of yeast NDI1, a ubiquinone oxidoreductase that allows bypass of Complex I function. Thus, we conclude that mtDNA mutations and impaired glucose utilization are potential biomarkers for identifying tumours with increased sensitivity to OXPHOS inhibitors.
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影响因子：
11.2
作者：
Javeshghani, Shiva;Zakikhani, Mahvash;Pollak, Michael N.
通讯作者：
Pollak, Michael N.
影响因子：
4.8
作者：
El-Mir, MY;Nogueira, V;Leverve, X
通讯作者：
Leverve, X
影响因子：
64.8
作者：
Possemato, Richard;Marks, Kevin M.;Shaul, Yoav D.;Pacold, Michael E.;Kim, Dohoon;Birsoy, Kivanc;Sethumadhavan, Shalini;Woo, Hin-Koon;Jang, Hyun G.;Jha, Abhishek K.;Chen, Walter W.;Barrett, Francesca G.;Stransky, Nicolas;Tsun, Zhi-Yang;Cowley, Glenn S.;Barretina, Jordi;Kalaany, Nada Y.;Hsu, Peggy P.;Ottina, Kathleen;Chan, Albert M.;Yuan, Bingbing;Garraway, Levi A.;Root, David E.;Mino-Kenudson, Mari;Brachtel, Elena F.;Driggers, Edward M.;Sabatini, David M.
通讯作者：
Sabatini, David M.
影响因子：
50.3
作者：
Shackelford DB;Abt E;Gerken L;Vasquez DS;Seki A;Leblanc M;Wei L;Fishbein MC;Czernin J;Mischel PS;Shaw RJ
通讯作者：
Shaw RJ
影响因子：
--
作者：
Hall A;Meyle KD;Lange MK;Klima M;Sanderhoff M;Dahl C;Abildgaard C;Thorup K;Moghimi SM;Jensen PB;Bartek J;Guldberg P;Christensen C
通讯作者：
Christensen C