Metabolic state of glioma stem cells and nontumorigenic cells
Metabolic state of glioma stem cells and nontumorigenic cells
复制标题
DOI：
10.1073/pnas.1106704108
复制
发表时间：
2011-09-20
影响因子：
11.1
通讯作者：
Pajonk, Frank
中科院分区：
文献类型：
--
作者：
Vlashi, Erina;Lagadec, Chann;Pajonk, Frank
神经胶质瘤含有少量的治疗抗性神经胶质瘤干细胞（GSC），并且认为肿瘤再生长起源于GSC，从而使GSC成为新治疗方法的有吸引力的靶点。对于葡萄糖代谢，癌细胞更多地依赖于糖酵解而不是氧化磷酸化，这是在实体癌的2-[（18）F]氟-2-脱氧-D-葡萄糖正电子发射断层扫描成像中使用的现象，并且靶向癌细胞中的代谢途径已经成为相当感兴趣的主题。然而，如果GSC确实对肿瘤控制很重要，则需要了解GSC的代谢状态。我们假设GSC的代谢与其后代的代谢不同。使用一个独特的成像系统的GSC，我们评估了耗氧率，细胞外酸化率，细胞内ATP水平，葡萄糖摄取，乳酸生产，PKM 1和PKM 2的表达，辐射敏感性，和细胞周期持续时间的GSC和他们的后代在一组胶质瘤细胞系。我们发现GSC和祖细胞比分化的胶质瘤细胞糖酵解更少。GSC消耗更少的葡萄糖，产生更少的乳酸，同时保持更高的ATP水平比他们的分化后代。与分化的细胞相比，GSCs具有放射抗性，这与较高的线粒体储备能力有关。胶质瘤细胞表达丙酮酸激酶的两种亚型，抑制糖酵解或氧化磷酸化对GSC和祖细胞的能量产生影响最小。我们的结论是，GSCs主要依赖于氧化磷酸化。然而，如果受到挑战，它们可以使用其他代谢途径。因此，在胶质瘤中靶向糖酵解可能会使GSC免于受损伤。
Gliomas contain a small number of treatment-resistant glioma stem cells (GSCs), and it is thought that tumor regrowth originates from GSCs, thus rendering GSCs an attractive target for novel treatment approaches. Cancer cells rely more on glycolysis than on oxidative phosphorylation for glucose metabolism, a phenomenon used in 2-[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography imaging of solid cancers, and targeting metabolic pathways in cancer cells has become a topic of considerable interest. However, if GSCs are indeed important for tumor control, knowledge of the metabolic state of GSCs is needed. We hypothesized that the metabolism of GSCs differs from that of their progeny. Using a unique imaging system for GSCs, we assessed the oxygen consumption rate, extracellular acidification rate, intracellular ATP levels, glucose uptake, lactate production, PKM1 and PKM2 expression, radiation sensitivity, and cell cycle duration of GSCs and their progeny in a panel of glioma cell lines. We found GSCs and progenitor cells to be less glycolytic than differentiated glioma cells. GSCs consumed less glucose and produced less lactate while maintaining higher ATP levels than their differentiated progeny. Compared with differentiated cells, GSCs were radioresistant, and this correlated with a higher mitochondrial reserve capacity. Glioma cells expressed both isoforms of pyruvate kinase, and inhibition of either glycolysis or oxidative phosphorylation had minimal effect on energy production in GSCs and progenitor cells. We conclude that GSCs rely mainly on oxidative phosphorylation. However, if challenged, they can use additional metabolic pathways. Therefore, targeting glycolysis in glioma may spare GSCs.