The role of cellular oxidative stress in regulating glycolysis energy metabolism in hepatoma cells.
BACKGROUND
The 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.


METHODS
Various 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).


RESULTS
We 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.


CONCLUSIONS
This 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.
Shi
Dong-yun
DY
Department of Biochemistry and Molecular Biology, Shanghai Medical College of Fudan University, Free Radical Regulation and Application Research Center of Fudan University, Shanghai 200032, PR China. dongyunshi@yahoo.com.cn
Xie
Fei-zhou
FZ
Zhai
Chao
C
Stern
Jeremy S
JS
Liu
Yang
Y
Liu
Shan-lin
SL
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D003627:Data Interpretation, Statistical; D006019:Glycolysis; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism
D017382:Reactive Oxygen Species; D007770:L-Lactate Dehydrogenase; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase