The role of cellular oxidative stress in regulating glycolysis energy metabolism in hepatoma cells.
The role of cellular oxidative stress in regulating glycolysis energy metabolism in hepatoma cells.
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细胞氧化应激在调节肝癌细胞糖酵解能量代谢中的作用
DOI：
10.1186/1476-4598-8-32
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发表时间：
2009-06-05
期刊：
影响因子：
37.3
通讯作者：
Liu SL
中科院分区：
文献类型：
--
作者：
Shi DY;Xie FZ;Zhai C;Stern JS;Liu Y;Liu SL
研究背景Warburg效应在多种人类癌症中被发现，但其潜在的机制尚不清楚。本研究旨在探讨细胞氧化应激在肝癌细胞糖酵解和Warburg效应中的作用。方法采用多种细胞系结合环境缺氧作为体外模型，模拟体内肿瘤微环境。用超氧化物歧化酶(SOD)和黄嘌呤氧化酶(XO)基因转染产生不同水平的细胞氧化还原。用2‘，7’-二氯荧光素(DCF)荧光和ESR光谱检测细胞内活性氧(ROS)。结果内源性或外源性对细胞氧化应激的干扰均能灵敏地调节肝癌细胞的糖酵解和Warburg效应。与永生化的正常肝细胞相比，肝癌细胞显示出高水平的自由基。增加肝癌细胞的ROS应激水平可以直接上调HIF-1并激活糖酵解，而不需要低氧条件。这解释了有氧糖酵解的机制，即沃堡效应的产生。无论是内源性上调SOD，还是外源性给予抗氧化剂，均可通过下调ROS水平有效地调节肝癌细胞的能量通路，抑制肿瘤细胞和移植瘤的生长。结论本研究提示Warburg效应与细胞内ROS和HIF-1水平升高有关。肝癌细胞为了适应低氧生存和快速生长，利用氧化应激异位激活的糖酵解来补偿能量供应。肿瘤细胞通过细胞氧化应激激活糖酵解以满足其能量代谢需求的这一特定机制可用于选择性杀伤肿瘤细胞。
BackgroundThe Warburg effect has been found in a wide spectrum of human cancers, however the underlying mechanisms are still unclear. This study aims to explore the role of cellular oxidative stress in relation to glycolysis and the Warburg effect in hepatoma cells.MethodsVarious cell lines combining environmental hypoxia was used as an in vitro model to mimic tumor microenvironment in vivo. Superoxide dismutases (SOD) and xanthine oxidase (XO) gene transfection were used to produce various cellular redox levels. 2',7'-dichlorofluorescin (DCF) fluorescence and ESR spectrum were used to detect cellular reactive oxygen species (ROS).ResultsWe found that endogenous or exogenous interference with the cellular oxidative stress can sensitively regulate glycolysis and the Warburg effect in hepatoma cells. Hepatoma cells displayed a high level of free radicals compared to immortalized normal hepatocyte cells. Increasing the level of ROS stress in hepatoma cells can directly upregulate HIF-1 and activate glycolysis without requirement of a hypoxic condition. This explains the mechanism whereby aerobic glycolysis, i.e. the Warburg effect arises. Either endogenously upregulating SOD or exogenously administration with antioxidant can, through downregulating ROS level, effectively regulate energy pathways in hepatoma cells and can inhibit the growth of tumor cells and xenograft tumors.ConclusionThis study suggests that the Warburg effect was related to an inherently high level of cellular ROS and HIF-1. Hepatoma cells adaptation to hypoxia for survival and rapid growth exploits oxidative stress ectopically activated glycolysis to compensate the energy supply. This specific mechanism in which tumor cells through cellular oxidative stress activate glycolysis to meet their energy metabolism requirement could be exploited to selectively kill tumor cells.
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DOI：
10.1073/pnas.0402088101
发表时间：
2004-05-25
影响因子：
11.1
作者：
Koike, T;Kimura, N;Kanangi, R
通讯作者：
Kanangi, R
影响因子：
6.1
作者：
Lin, SB;Li, CH;Kan, LS
通讯作者：
Kan, LS
影响因子：
3.9
作者：
Liu, SL;Lin, X;Zhang, YD
通讯作者：
Zhang, YD
影响因子：
11.2
作者：
Kumar, Binod;Koul, Sweaty;Koul, Hari K.
通讯作者：
Koul, Hari K.
DOI：
10.1053/ejso.2001.1237
发表时间：
2002-04-01
期刊：
EUROPEAN JOURNAL OF SURGICAL ONCOLOGY
影响因子：
--
作者：
Chen, CJ;Tsai, NM;Harn, HJ
通讯作者：
Harn, HJ