Increased OXPHOS activity precedes rise in glycolytic rate in H-RasV12/E1A transformed fibroblasts that develop a Warburg phenotype.
Increased OXPHOS activity precedes rise in glycolytic rate in H-RasV12/E1A transformed fibroblasts that develop a Warburg phenotype.
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DOI：
10.1186/1476-4598-8-54
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发表时间：
2009-07-31
期刊：
影响因子：
37.3
通讯作者：
Wieringa B
中科院分区：
文献类型：
--
作者：
de Groof AJ;te Lindert MM;van Dommelen MM;Wu M;Willemse M;Smift AL;Winer M;Oerlemans F;Pluk H;Fransen JA;Wieringa B
癌细胞中的Warburg表型早已被认识到，但对其建立特征的连续代谢改变的了解仍然有限。我们通过研究衰老丧失或H-RasV12/ e1a转化表型的小鼠胚胎成纤维细胞来源的细胞在不同的致癌进展阶段，更好地了解了代谢与恶性转化之间的耦合。自发永生化或诱导衰老-旁路对代谢谱和生存能力只有边际影响。相比之下，H-RasV12/E1A转化最初引起氧气消耗和超氧化物产生的急剧增加，伴随着大量细胞死亡。随着体外培养时间的延长，免疫缺陷小鼠的体外不依赖锚定生长试验和体内肿瘤形成试验中，细胞生长速度逐渐增加，形成肿瘤的潜力也逐渐增加。值得注意的是，葡萄糖-乳酸通量随着传代次数的增加而增加，而细胞耗氧量则减少。这种代谢特性的转换与线粒体NAD+/NADH氧化还原的变化有关，表明线粒体三羧酸循环和OXPHOS活性降低。新转化细胞的高氧化代谢率与肿瘤后期细胞的高糖酵解率形成鲜明对比。在我们的实验系统中，细胞在富营养的环境氧条件下生长，向这种Warburg表型的转变是一个循序渐进的适应过程，与转化细胞的致瘤能力增强和生存特性改善有关。我们推测，早期转化的细胞可能会逃避针对具有完全发育的Warburg表型的肿瘤进行代谢抑制的治疗。
The Warburg phenotype in cancer cells has been long recognized, but there is still limited insight in the consecutive metabolic alterations that characterize its establishment. We obtained better understanding of the coupling between metabolism and malignant transformation by studying mouse embryonic fibroblast-derived cells with loss-of-senescence or H-RasV12/E1A-transformed phenotypes at different stages of oncogenic progression. Spontaneous immortalization or induction of senescence-bypass had only marginal effects on metabolic profiles and viability. In contrast, H-RasV12/E1A transformation initially caused a steep increase in oxygen consumption and superoxide production, accompanied by massive cell death. During prolonged culture in vitro, cell growth rate increased gradually, along with tumor forming potential in in vitro anchorage-independent growth assays and in vivo tumor formation assays in immuno-deficient mice. Notably, glucose-to-lactic acid flux increased with passage number, while cellular oxygen consumption decreased. This conversion in metabolic properties was associated with a change in mitochondrial NAD+/NADH redox, indicative of decreased mitochondrial tricarboxic acid cycle and OXPHOS activity. The high rate of oxidative metabolism in newly transformed cells is in marked contrast with the high glycolytic rate in cells in the later tumor stage. In our experimental system, with cells growing under ambient oxygen conditions in nutrient-rich media, the shift towards this Warburg phenotype occurred as a step-wise adaptation process associated with augmented tumorigenic capacity and improved survival characteristics of the transformed cells. We hypothesize that early-transformed cells, which potentially serve as founders for new tumor masses may escape therapies aimed at metabolic inhibition of tumors with a fully developed Warburg phenotype.
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影响因子：
3.4
作者：
de Groof, AJC;Oerlemans, FTJJ;Wieringa, B
通讯作者：
Wieringa, B
DOI：
10.1073/pnas.1633591100
发表时间：
2003-08-05
影响因子：
11.1
作者：
Fjeld, CC;Birdsong, WT;Goodman, RH
通讯作者：
Goodman, RH
DOI：
10.1073/pnas.0700690104
发表时间：
2007-04-10
影响因子：
11.1
作者：
Funes, Juan M.;Quintero, Marisol;Boshoff, Chris
通讯作者：
Boshoff, Chris
影响因子：
3.5
作者：
Levitt, Jonathan M.;Baldwin, Amy;Georgakoudi, Irene
通讯作者：
Georgakoudi, Irene
影响因子：
3.7
作者：
Alexandrova, Antonina Y.;Kopnin, Pauel B.;Kopnin, Boris P.
通讯作者：
Kopnin, Boris P.