Breast cancer stem cells rely on fermentative glycolysis and are sensitive to 2-deoxyglucose treatment.
Breast cancer stem cells rely on fermentative glycolysis and are sensitive to 2-deoxyglucose treatment.
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DOI：
10.1038/cddis.2014.285
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发表时间：
2014-07-17
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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作者：
许多研究表明，癌症干细胞对肿瘤生长至关重要，如果不能针对这些细胞，可能会导致肿瘤复发。由于这种细胞群已被证明对放射和化疗具有抵抗力，因此了解它们的生物学并确定新的治疗方法是至关重要的。靶向肿瘤代谢是对抗肿瘤生长和复发的一种潜在的替代策略。在这里，我们应用蛋白质组学和靶向代谢组学分析，以指出乳腺癌细胞生长为球形并因此富含癌症干细胞的主要代谢差异，并与在贴壁分化条件下生长的相同细胞进行比较。这一综合方法使我们能够确定与干细胞性疾病相关的代谢表型，并表明乳腺癌干细胞(BCSCs)从线粒体氧化磷酸化转变为发酵糖酵解。蛋白质组学和代谢数据的功能验证为肿瘤干细胞中厌氧葡萄糖命运的关键酶，如丙酮酸激酶M2亚型、乳酸脱氢酶和葡萄糖6-磷酸脱氢酶的活性增加以及不同的氧化还原状态提供了证据。此外，我们发现，2-脱氧葡萄糖，一种众所周知的糖酵解抑制剂，在单独使用时抑制BCSC的增殖，当与阿霉素联合使用时显示出协同作用。总之，我们认为抑制糖酵解可能是靶向BCSCs的一种潜在的有效策略。
A number of studies suggest that cancer stem cells are essential for tumour growth, and failure to target these cells can result in tumour relapse. As this population of cells has been shown to be resistant to radiation and chemotherapy, it is essential to understand their biology and identify new therapeutic approaches. Targeting cancer metabolism is a potential alternative strategy to counteract tumour growth and recurrence. Here we applied a proteomic and targeted metabolomic analysis in order to point out the main metabolic differences between breast cancer cells grown as spheres and thus enriched in cancer stem cells were compared with the same cells grown in adherent differentiating conditions. This integrated approach allowed us to identify a metabolic phenotype associated with the stem-like condition and shows that breast cancer stem cells (BCSCs) shift from mitochondrial oxidative phosphorylation towards fermentative glycolysis. Functional validation of proteomic and metabolic data provide evidences for increased activities of key enzymes of anaerobic glucose fate such as pyruvate kinase M2 isoform, lactate dehydrogenase and glucose 6-phopshate dehydrogenase in cancer stem cells as well as different redox status. Moreover, we show that treatment with 2-deoxyglucose, a well known inhibitor of glycolysis, inhibits BCSC proliferation when used alone and shows a synergic effect when used in combination with doxorubicin. In conclusion, we suggest that inhibition of glycolysis may be a potentially effective strategy to target BCSCs.
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DOI：
10.1126/science.1211485
发表时间：
2011-12-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Anastasiou D;Poulogiannis G;Asara JM;Boxer MB;Jiang JK;Shen M;Bellinger G;Sasaki AT;Locasale JW;Auld DS;Thomas CJ;Vander Heiden MG;Cantley LC
通讯作者：
Cantley LC
影响因子：
56.9
作者：
Dennis, PB;Jaeschke, A;Thomas, G
通讯作者：
Thomas, G
影响因子：
9
作者：
通讯作者：
--
DOI：
10.1126/science.1188015
发表时间：
2010-09-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Vander Heiden MG;Locasale JW;Swanson KD;Sharfi H;Heffron GJ;Amador-Noguez D;Christofk HR;Wagner G;Rabinowitz JD;Asara JM;Cantley LC
通讯作者：
Cantley LC
DOI：
10.1016/j.jchromb.2008.04.049
发表时间：
2008-08-15
影响因子：
3
作者：
Kanani, Harin;Chrysanthopoulos, Panagiotis K.;Klapa, Maria I.
通讯作者：
Klapa, Maria I.